PEGylated Bilirubin-coated Iron Oxide Nanoparticles as a Biosensor for Magnetic Relaxation Switching-based ROS Detection in Whole Blood.
Lee Dong Yun,Kang Sukmo,Lee Yonghyun,Kim Jin Yong,Yoo Dohyun,Jung Wonsik,Lee Soyoung,Jeong Yong Yeon,Lee Kwangyeol,Jon Sangyong
Theranostics
: Magnetic relaxation switching (MRSw) induced by target-triggered aggregation or dissociation of superparamagnetic iron oxide nanoparticles (SPIONs) have been utilized for detection of diverse biomarkers. However, an MRSw-based biosensor for reactive oxygen species (ROS) has never been documented. : To this end, we constructed a biosensor for ROS detection based on PEGylated bilirubin (PEG-BR)-coated SPIONs (PEG-BR@SPIONs) that were prepared by simple sonication via ligand exchange. In addition, near infra-red (NIR) fluorescent dye was loaded onto PEG-BR@SPIONs as a secondary option for fluorescence-based ROS detection. Resul: PEG-BR@SPIONs showed high colloidal stability under physiological conditions, but upon exposure to the model ROS, NaOCl, , they aggregated, causing a decrease in signal intensity in T2-weighted MR images. Furthermore, ROS-responsive PEG-BR@SPIONs were taken up by lipopolysaccharide (LPS)-activated macrophages to a much greater extent than ROS-unresponsive control nanoparticles (PEG-DSPE@SPIONs). In a sepsis-mimetic clinical setting, PEG-BR@SPIONs were able to directly detect the concentrations of ROS in whole blood samples through a clear change in T2 MR signals and a 'turn-on' signal of fluorescence. : These findings suggest that PEG-BR@SPIONs have the potential as a new type of dual mode (MRSw-based and fluorescence-based) biosensors for ROS detection and could be used to diagnose many diseases associated with ROS overproduction.
10.7150/thno.39662
Multifunctional motion-to-color janus transducers for the rapid detection of sepsis biomarkers in whole blood.
Russell Steven M,Alba-Patiño Alejandra,Borges Marcio,de la Rica Roberto
Biosensors & bioelectronics
Self-propelled particles are revolutionizing sensing applications thanks to a unique motion-based signal generation mechanism in which biorecognition reactions are detected as changes in the velocity of the colloids. Here a new family of self-propelled multifunctional Janus particles is introduced that enables detecting changes in particle motion colorimetrically. The particles consist of an iron oxide core that provides color and magnetism, and a Janus coating that provides biospecific recognition and locomotive properties. In this approach, biomolecular interactions trigger changes in particle motion that are detected as variations in color when spotted on a piece of paper. These variations in color are then read and quantified with a custom-made smartphone app. The high surface area and magnetism of the particles makes them ideal building blocks for developing biosensors because they allow for the rapid capture of a target molecule and the removal of non-specific interactions. Biosensors engineered with the proposed multifunctional particles were able to detect the sepsis biomarker procalcitonin at clinically relevant concentrations within 13 min in whole blood, which is faster than other approaches requiring hour-long incubation steps under controlled conditions to detect the same biomarker in purified serum. The short assay time along with the point-of-need design makes these biosensors suitable for stratifying patients according to their sepsis risk level during triage independently of resource constraints.
10.1016/j.bios.2019.111346
Human Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis.
mBio
is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of -encoded mAbs blocks heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of -encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against infection. The human pathogen causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region gene-encoded human monoclonal antibodies with the response against IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB.
10.1128/mBio.02473-19
Severe Yellow Fever and Extreme Hyperferritinemia Managed with Therapeutic Plasma Exchange.
Sztajnbok Jaques,Sant'Ana Malaque Ceila Maria,Nihei Camila Hitomi,Duayer Irene Faria,Leme Britto Zita Maria,Beraldo Eduarda Gambini,AzevedoTeixeira Ralcyon Francis
The American journal of tropical medicine and hygiene
A 43-year-old man was admitted to the intensive care unit and diagnosed with yellow fever. He presented with refractory bleeding, extreme hyperferritinemia, and multiple organ dysfunction syndrome, requiring renal replacement therapy, mechanical ventilation, and treatment with vasoactive drugs. Because the bleeding did not respond to fresh-frozen plasma administration, the patient received therapeutic plasma exchange, which was accompanied by a marked improvement of the clinical and biochemical parameters, including a significant decline in serum ferritin levels.
10.4269/ajtmh.19-0219
Deciphering ferroptosis in critical care: mechanisms, consequences, and therapeutic opportunities.
Frontiers in immunology
Ischemia-reperfusion injuries (IRI) across various organs and tissues, along with sepsis, significantly contribute to the progression of critical illnesses. These conditions disrupt the balance of inflammatory mediators and signaling pathways, resulting in impaired physiological functions in human tissues and organs. Ferroptosis, a distinct form of programmed cell death, plays a pivotal role in regulating tissue damage and modulating inflammatory responses, thereby influencing the onset and progression of severe illnesses. Recent studies highlight that pharmacological agents targeting ferroptosis-related proteins can effectively mitigate oxidative stress caused by IRI in multiple organs, alleviating associated symptoms. This manuscript delves into the mechanisms and signaling pathways underlying ferroptosis, its role in critical illnesses, and its therapeutic potential in mitigating disease progression. We aim to offer a novel perspective for advancing clinical treatments for critical illnesses.
10.3389/fimmu.2024.1511015
In vivo bioluminescence imaging of labile iron pools in a murine model of sepsis with a highly selective probe.
Feng Ping,Ma Lin,Xu Feng,Gou Xueyan,Du Lupei,Ke Bowen,Li Minyong
Talanta
Iron plays an essential role in biological system. An approach for in vivo imaging of this metal ion is needed to investigate its complex contributions to physiological and pathological processes. Herein, we present a bioluminescent probe FP-1 as a powerful tool for targeting Fe detection in vitro and in vivo. The turn-on sensing scheme is based on the caged strategy of luciferin-luciferase system. FP-1 not only can detect accumulations of exogenous Fe in living animal, but also has the capability of monitoring labile endogenous Fe levels in animal model of sepsis. Implementation of this technique provides a valuable opportunity for understanding underlying mechanisms of Fe in biological processes and disease states.
10.1016/j.talanta.2019.05.017
Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still's disease: A multicenter retrospective study.
Kirino Yohei,Kawaguchi Yasushi,Tada Yoshifumi,Tsukamoto Hiroshi,Ota Toshiyuki,Iwamoto Masahiro,Takahashi Hiroki,Nagasawa Kohei,Takei Shuji,Horiuchi Takahiko,Ichida Hisae,Minota Seiji,Ueda Atsuhisa,Ohta Akihide,Ishigatsubo Yoshiaki
Modern rheumatology
BACKGROUND:Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. METHODS:Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. RESULTS:Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. CONCLUSION:We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria.
10.1080/14397595.2017.1422231
Exploitation of two siderophore receptors, BauA and BfnH, for protection against Acinetobacter baumannii infection.
Aghajani Zahra,Rasooli Iraj,Mousavi Gargari Seyed Latif
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
Iron uptake system is expressed in early stages of Acinetobacter baumannii infections under iron-restricted conditions. This study is aimed at the evaluation of immuno-protectivity of BfnH in comparison with BauA in both mature and selected fragmental proteins. The study was designed in single and combined forms of antigens. BfnH is presented in 3472 strains of A. baumannii with more than 97% identity. The preliminary immune-informatics analysis of this protein indicated a region from the β-barrel domain including exposed loops 2-5, with antigenic score comparable to that of BfnH. There was a significant rise in the specific IgG response in all test groups. The bacterial challenge with a lethal dose of A. baumannii demonstrated partial protection of whole proteins which coincides with a significant reduction in the bacterial population colonized in the main organs and an increase in the survival level. Passive immunization of the mice brought about 50% survival in the mice groups immunized with BfnH and with a combination of BfnH and BauA. The protectivity of siderophore receptors suggests their potential immunogenic role that could be considered as a component of multivalent subunit vaccine candidates against A. baumannii.
10.1111/apm.12992
A Klebsiella pneumoniae ST307 outbreak clone from Germany demonstrates features of extensive drug resistance, hypermucoviscosity, and enhanced iron acquisition.
Genome medicine
BACKGROUND:Antibiotic-resistant Klebsiella pneumoniae are a major cause of hospital- and community-acquired infections, including sepsis, liver abscess, and pneumonia, driven mainly by the emergence of successful high-risk clonal lineages. The K. pneumoniae sequence type (ST) 307 lineage has appeared in several different parts of the world after first being described in Europe in 2008. From June to October 2019, we recorded an outbreak of an extensively drug-resistant ST307 lineage in four medical facilities in north-eastern Germany. METHODS:Here, we investigated these isolates and those from subsequent cases in the same facilities. We performed whole-genome sequencing to study phylogenetics, microevolution, and plasmid transmission, as well as phenotypic experiments including growth curves, hypermucoviscosity, siderophore secretion, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance for an in-depth characterization of this outbreak clone. RESULTS:Phylogenetics suggest a homogenous phylogram with several sub-clades containing either isolates from only one patient or isolates originating from different patients, suggesting inter-patient transmission. We identified three large resistance plasmids, carrying either NDM-1, CTX-M-15, or OXA-48, which K. pneumoniae ST307 likely donated to other K. pneumoniae isolates of different STs and even other bacterial species (e.g., Enterobacter cloacae) within the clinical settings. Several chromosomally and plasmid-encoded, hypervirulence-associated virulence factors (e.g., yersiniabactin, metabolite transporter, aerobactin, and heavy metal resistance genes) were identified in addition. While growth, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance were comparable to several control strains, results from siderophore secretion and hypermucoviscosity experiments revealed superiority of the ST307 clone, similar to an archetypical, hypervirulent K. pneumoniae strain (hvKP1). CONCLUSIONS:The combination of extensive drug resistance and virulence, partly conferred through a "mosaic" plasmid carrying both antibiotic resistance and hypervirulence-associated features, demonstrates serious public health implications.
10.1186/s13073-020-00814-6
Hepcidin, an Iron Regulatory Hormone of Innate Immunity, is Differentially Expressed in Premature Fetuses with Early-Onset Neonatal Sepsis.
Tabbah Sammy M,Buhimschi Catalin S,Rodewald-Millen Katherine,Pierson Christopher R,Bhandari Vineet,Samuels Philip,Buhimschi Irina A
American journal of perinatology
OBJECTIVE:Hepcidin, a mediator of innate immunity, binds the iron exporter ferroportin, leading to functional hypoferremia through intracellular iron sequestration. We explored hepcidin-ferroportin interactions in neonates clinically diagnosed with early-onset neonatal sepsis (EONS). STUDY DESIGN:Hepcidin and interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay (ELISA) in 92 paired cord blood-maternal blood samples in the following groups: "Yes" EONS ( = 41, gestational age [GA] 29 ± 1 weeks) and "No" EONS ( = 51, GA 26 ± 1 weeks). Placental hepcidin and ferroportin expression were evaluated by immunohistochemistry and real-time-polymerase chain reaction (RT-PCR). Liver hepcidin and ferroportin expression patterns were ascertained in autopsy specimens of neonates ( = 8) who died secondary to culture-proven sepsis. RESULTS:Cord blood hepcidin was significantly elevated (GA corrected, = 0.018) and was positively correlated with IL-6 ( = 0.379, = 0.001) in EONS. Hepcidin localized at syncytiotrophoblast and fetal vascular endothelium. Placental ferroportin, but not hepcidin mRNA correlated with cord blood hepcidin levels ( = 0.46, = 0.039) and funisitis severity ( = 0.50, = 0.018). Newborns who died from sepsis ( = 4) had higher hepatic hepcidin and iron sequestration, but lower ferroportin staining than those who died of nonsepsis causes ( = 4). CONCLUSION:Premature fetuses with EONS have elevated circulating hepcidin, likely related to lower placenta and liver ferroportin expression. Fetal hepcidin-ferroportin interaction appears to play a role in EONS pathophysiology independent of maternal response to intrauterine inflammation.
10.1055/s-0038-1626711
Inflammatory anemia-associated parameters are related to 28-day mortality in patients with sepsis admitted to the ICU: a preliminary observational study.
Jiang Yi,Jiang Feng-Quan,Kong Fang,An Meng-Meng,Jin Bei-Bei,Cao Da,Gong Ping
Annals of intensive care
BACKGROUND:Anemia is one of the most common complications of sepsis. Sepsis-related anemia is associated mainly with inflammation. We aimed to observe the changes in the inflammatory anemia-associated parameters of patients with sepsis in the early stage of intensive care unit (ICU) admission and to evaluate their association with 28-day mortality. METHODS:A total of 198 patients with sepsis were divided into survivor (n = 110) and non-survivor (n = 88) groups on the basis of 28-day survival. Healthy volunteers (n = 20) were enrolled as a control group. Plasma levels of iron, ferritin, erythropoietin (EPO), soluble transferrin receptor (sTfR), hepcidin, interleukin-6 (IL-6), hemoglobin and the red blood cell distribution width (RDW) were measured on days 1, 3 and 7 of ICU admission. Clinical data and laboratory findings were collected, and the Sequential Organ Failure Assessment (SOFA) score was calculated. RESULTS:Patients with sepsis showed significant decreases in hemoglobin, plasma iron and sTfR/log ferritin and significant increases in plasma EPO, sTfR, hepcidin, ferritin and IL-6 on days 1, 3 and 7 of ICU admission compared with healthy volunteers. Hemoglobin was correlated negatively with plasma IL-6 and hepcidin. In patients with sepsis, non-survivors had significantly lower plasma iron, EPO and sTfR/log ferritin, but higher plasma hepcidin, ferritin and IL-6 than survivors on days 1, 3 and 7 of ICU admission. Plasma EPO, hepcidin, ferritin, IL-6, sTfR/log ferritin, the RDW and SOFA score were associated significantly with 28-day mortality but to a varying extent. In particular, in predicting 28-day mortality, plasma hepcidin had an area under the receiver operating curve of 0.808 and 87.3% specificity, which was the highest among the inflammatory anemia-associated parameters tested. CONCLUSIONS:Inflammatory anemia-associated parameters changed significantly in patients with sepsis in the first week of ICU admission. Plasma EPO, hepcidin, ferritin, IL-6, sTfR/log ferritin, the RDW and SOFA score were associated significantly with 28-day mortality. Plasma hepcidin might have a superior predictive value, with high specificity, compared with other inflammatory anemia-associated parameters for 28-day mortality of sepsis patients in the ICU.
10.1186/s13613-019-0542-7
Immunodominance of Epitopes and Protective Efficacy of HI Antigen Are Differentially Altered Using Different Adjuvants in a Mouse Model of Bacteremia.
Chen Zhifu,Gou Qiang,Xiong Qingshan,Duan Lianli,Yuan Yue,Zhu Jiang,Zou Jintao,Chen Longlong,Jing Haiming,Zhang Xiaoli,Luo Ping,Zeng Hao,Zou Quanming,Zhao Zhuo,Zhang Jinyong
Frontiers in immunology
HI, a fusion protein that consists of the alpha-toxin (Hla) and the N2 domain of iron surface determinant B (IsdB), is one of the antigens in the previously reported vaccine rFSAV and has already entered phase II clinical trials. Previous studies revealed that HI is highly immunogenic in both mice and healthy volunteers, and the humoral immune response plays key roles in HI-mediated protection. In this study, we further investigated the protective efficacy of immunization with HI plus four different adjuvants in a mouse bacteremia model. Results showed that HI-mediated protection was altered in response to different adjuvants. Using antisera from immunized mice, we identified seven B-cell immunodominant epitopes on Hla and IsdB, including 6 novel epitopes (Hla, Hla, Hla, IsdB, IsdB, and IsdB). The immunodominance of B-cell epitopes, total IgG titers and the levels of IFN-γ and IL-17A from mice immunized with HI plus different adjuvants were different from each other, which may explain the difference in protective immunity observed in each immunized group. Thus, our results indicate that adjuvants largely affected the immunodominance of epitopes and the protective efficacy of HI, which may guide further adjuvant screening for vaccine development and optimization.
10.3389/fimmu.2021.684823
An Enzyme-Mimicking Single-Atom Catalyst as an Efficient Multiple Reactive Oxygen and Nitrogen Species Scavenger for Sepsis Management.
Cao Fangfang,Zhang Lu,You Yawen,Zheng Lirong,Ren Jinsong,Qu Xiaogang
Angewandte Chemie (International ed. in English)
Sepsis, characterized by immoderate production of multiple reactive oxygen and nitrogen species (RONS), causes high morbidity and mortality. Despite progress made with nanozymes, efficient antioxidant therapy to eliminate these RONS remains challenging, owing largely to the specificity and low activity of exploited nanozymes. Herein, an enzyme-mimicking single-atom catalyst, Co/PMCS, features atomically dispersed coordinatively unsaturated active Co-porphyrin centers, which can rapidly obliterate multiple RONS to alleviate sepsis. Co/PMCS can eliminate O and H O by mimicking superoxide dismutase, catalase, and glutathione peroxidase, while removing OH via the oxidative-reduction cycle, with markedly higher activity than nanozymes. It can also scavenge NO through formation of a nitrosyl-metal complex. Eventually, it can reduce proinflammatory cytokine levels, protect organs from damage, and confer a distinct survival advantage to the infected sepsis mice.
10.1002/anie.201912182
Iron supplementation in anemic Zanzibari toddlers is associated with greater loss in erythrocyte iron isotope enrichment.
The American journal of clinical nutrition
BACKGROUND:Heavy parasitic loads increase the risk of iron (Fe) deficiency anemia, which remains prevalent globally. Where parasites are common, understanding the influence of parasitic infections on Fe incorporation and erythropoiesis in toddlers is especially important. OBJECTIVES:The aim of this study was to identify the impacts of malarial and helminth infections on red blood cell (RBC) Fe incorporation and subsequent changes in RBC Fe isotope enrichment for 84 days postdosing in toddlers at high risk for parasitic infections. METHODS:Fe incorporation was measured in a group of Zanzibari toddlers (n = 71; 16-25 months) using a stable Fe isotopic method. At study entry, an oral stable Fe isotope was administered. Blood was collected 14 (D14) and 84 (D84) days postdosing for the assessment of Fe status indicators and RBC isotopic enrichment. Blood and stool samples were collected and screened for malaria and helminth parasites. Factors associated with changes in RBC Fe isotope enrichment were identified using regression models. RESULTS:Toddlers who had larger weight-for-age z-scores, lower total body Fe, and helminth infections (n = 26) exhibited higher RBC Fe incorporation. RBC Fe isotope enrichment decreased from D14 to D84 by -2.75 percentage points (P < 0.0001; n = 66). Greater loss in RBC Fe isotope enrichment from D14 to D84 was observed in those who received Fe supplementation, those with either helminths or both malarial and helminth infections, and in those with greater RBC Fe incorporation on D14. CONCLUSIONS:Toddlers who received Fe supplementation exhibited significantly greater losses of RBC Fe isotope enrichment over time. We speculate this greater loss of RBC Fe enrichment is indicative of increased erythropoiesis due to the provision of Fe among anemic or helminth-infected toddlers.
10.1093/ajcn/nqab044
Serum Ferritin Predicts Neither Organ Dysfunction Nor Mortality in Pediatric Sepsis Due to Tropical Infections.
Williams Vijai,Menon Nisha,Bhatia Prateek,Biswal Manisha,Sreedharanunni Sreejesh,Rawat Amit,Jayashree Muralidharan,Nallasamy Karthi
Frontiers in pediatrics
To evaluate serial ferritin levels measured in the initial 72 h of admission as a biomarker for new and progressive multi organ dysfunction syndrome (NPMODS) and mortality (unfavorable outcomes) in critically ill children with sepsis due to tropical infections. In this prospective observational study from a tertiary care teaching hospital in India, children 3 month to 12 years with a diagnosis of acute febrile illness and any two features suggesting tropical infections [cytopenia (platelet count <1,00,000/cu.mm, total leucocyte count <4,000/cu.mm), hepatomegaly and/or splenomegaly, lymphadenopathy, systemic signs (rash, edema), respiratory distress, and encephalopathy not accounted by localized infection] were eligible for inclusion. Children with known or suspected disorder of iron metabolism were excluded. Primary outcome was to determine the association of serial ferritin levels with mortality and NPMODS. Secondary outcomes included estimation of the prevalence of hyperferritinemia and comparison of risk prediction scores with serial ferritin measurement in predicting unfavorable outcomes. In the 202 children enrolled, diagnosis could be established in 133 (65.8%) children. Scrub typhus and dengue were the most common infections. Median (IQR) ferritin measured at admission ( = 183) and on day 3 ( = 120) of hospital stay were 798 (378, 3,205) μg/L and 429 (213,680) μg/L, respectively. Majority ( = 180, 89.1%) had MODS at admission defined as per International pediatric sepsis consensus conference. NPMODS occurred in 47 (23.3%) children of whom 37 (18.3%) died. Children with three or less organ dysfunctions had lower mortality. Neither admission ferritin values nor the percentage change over 72 h was different between children with favorable and unfavorable outcomes. Pediatric Risk of Mortality (PRISM-III) and daily Pediatric Logistic Organ Dysfunction score (dPELOD2 score) were significantly different in those with unfavorable outcomes. Admission ferritin levels and percentage change in 72 h had poor discriminatory power for mortality with AUC of 0.53 (0.53, 0.67) and 0.50 (0.50, 0.64), respectively. dPELOD2 had the best discriminatory power for mortality with AUC of 0.89 (0.89, 0.95). Serial ferritin estimation predicted neither organ dysfunction nor mortality in pediatric sepsis with tropical infections. dPELOD-2 and PRISM-III predicted unfavorable outcomes better than ferritin. The current diagnostic criteria for MODS overestimated organ dysfunctions in tropical infections and hence may need modification with further validation in this epidemiological cohort.
10.3389/fped.2020.607673
The Role of Iron in the Susceptibility of Neonatal Mice to Escherichia coli K1 Sepsis.
Michels Kathryn R,Lambrecht Nathalie J,Carson William F,Schaller Matthew A,Lukacs Nicholas W,Bermick Jennifer R
The Journal of infectious diseases
Sepsis from Escherichia coli expressing the K1 antigen is a leading cause of death in neonates. In a murine model, E. coli K1 grew rapidly in the peritoneal cavity of neonatal mice, causing fatal disease. In contrast, adult mice cleared the infection. Neonatal mice mounted a rapid and equivalent antimicrobial immune response compared to adult mice. Interestingly, peritoneal fluid from neonatal mice contained significantly more total iron than that of adult mice, which was sufficient to support enhanced E. coli growth. Transient iron overload in adult mice infected with E. coli resulted in 100% mortality. Maternal diet-induced mild iron deficiency decreased offspring peritoneal iron, decreased bacterial growth, and conferred protection against sepsis. Taken together, neonatal susceptibility to E. coli K1 sepsis is enhanced by a localized excess of peritoneal iron that allows for unchecked bacterial growth. Targeting this excess iron may provide a new therapeutic target in human patients.
10.1093/infdis/jiz282
Ginsenoside Rg1 induces ferroptosis by regulating the focal adhesion kinase/protein kinase B-forkhead box O3A signaling pathway and alleviates sepsis-induced myocardial damage.
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society
It is significant to note that 50% of patients with sepsis show cardiac insufficiency. Ginsenoside-Rg1 (G-Rg1) has been shown to have a cardiovascular protective effect. However, whether G-Rg1 is involved in the mechanism of action of sepsis-induced myocardial damage (SIMD) is unclear. This study aimed to investigate the protective effect of G-Rg1 on SIMD and to further investigate its mechanism and mechanisms of regulation of downstream pathways. An in vivo model of sepsis was established in mice by cecal ligation and puncture (CLP), and mice was administered intraperitoneally 35 or 70 mg/kg G-Rg1 after surgery. The damage to cardiac tissue was detected by hematoxylin and eosin (HE) staining. Forkhead transcription factor O subfamily member 3a (FOXO3A) in SIMD mice was detected by immunohistochemistry. Apoptosis in mouse myocardial tissue was determined by TUNEL staining. The effect of G-Rg1 on SIMD cardiomyocytes was evaluated by incubating the cells with lipopolysaccharide to induce inflammation as an in vitro model of SIMD. Cardiomyocyte viability and apoptosis were evaluated by cell counting kit-8 (CCK-8) and flow cytometry. Lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and Fe markers of heart damage were detected by the kit. The concentrations of tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β) in heart tissue and H9c2 cells were determined by ELISA. The factors related to the focal adhesion kinase (FAK)/protein kinase B (AKT)-FOXO3A signaling pathway were determined by RT-qPCR and Western blot. High-dose G-Rg1 had a significant inhibitory effect on SIMD mouse model and lipopolysaccharide (LPS)-induced H9c2 cardiomyocytes, reducing serum levels of LDH, CK-MB, and cTnI concentrations, which effectively alleviated SIMD. G-Rg1 restored the abnormally elevated levels of TNF-α, IL-1β, and iron ions and promoted the expression of anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) expression, inhibiting apoptosis and inflammatory responses. In addition, G-Rg1 reversed the inhibitory effect of G-Rg1 on LPS-induced H9c2 cardiomyocyte injury through activation of the FAK/AKT signaling pathway and up-regulation of FOXO3A. G-Rg1 promoted the activation of the FAK/AKT signalling pathway and up-regulation of the protein expression levels of pathway-associated proteins, p-FAK and p-AKT. Therefore, G-Rg1 mediated the FAK/AKT-FOXO3A signaling pathway and played a role in the treatment of SIMD. We conclude that G-Rg1 inhibited apoptosis and inflammation of cardiomyocytes induced by sepsis and reduced iron ion levels by regulating FAK/AKT-FOXO3A signaling pathway.
10.26402/jpp.2024.4.04
Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation.
Frontiers in immunology
Introduction:Major clinically relevant inflammatory events such as septic shock and severe COVID-19 trigger dynamic changes in the host immune system, presenting promising candidates for new biomarkers to improve precision diagnostics and patient stratification. Hepcidin, a master regulator of iron metabolism, has been intensively studied in many pathologies associated with immune system activation, however these data have never been compared to other clinical settings. Thus, we aimed to reveal the dynamics of iron regulation in various clinical settings and to determine the suitability of hepcidin and/or ferritin levels as biomarkers of inflammatory disease severity. Cohorts:To investigate the overall predictive ability of hepcidin and ferritin, we enrolled the patients suffering with three different diagnoses - in detail 40 patients with COVID-19, 29 patients in septic shock and eight orthopedic patients who were compared to nine healthy donors and all cohorts to each other. Results:We showed that increased hepcidin levels reflect overall immune cell activation driven by intrinsic stimuli, without requiring direct involvement of infection vectors. Contrary to hepcidin, ferritin levels were more strongly boosted by pathogen-induced inflammation - in septic shock more than four-fold and in COVID-19 six-fold in comparison to sterile inflammation. We also defined the predictive capacity of hepcidin-to-ferritin ratio with AUC=0.79 and = 0.03. Discussion:Our findings confirm that hepcidin is a potent marker of septic shock and other acute inflammation-associated pathologies and demonstrate the utility of the hepcidin-to-ferritin ratio as a predictor of mortality in septic shock, but not in COVID-19.
10.3389/fimmu.2023.1110540
Anemia Recovery After Lung Contusion, Hemorrhagic Shock, and Chronic Stress Is Gender-Specific in a Rat Model.
Surgical infections
Severe trauma and hemorrhagic shock lead to persistent anemia. Although biologic gender is known to modulate inflammatory responses after critical illness, the impact of gender on anemia recovery after injury remains unknown. The aim of this study was to identify gender-specific differences in anemia recovery after critical illness. Male and proestrus female Sprague-Dawley rats (n = 8-9 per group) were subjected to lung contusion and hemorrhagic shock (LCHS) or LCHS with daily chronic stress (LCHS/CS) compared with naïve. Hematologic data, bone marrow progenitor growth, and bone marrow and liver gene transcription were analyzed on day seven. Significance was defined as p < 0.05. Males lost substantial weight after LCHS and LCHS/CS compared with naïve males, while female LCHS rats did not compared with naive counterparts. Male LCHS rats had a drastic decrease in hemoglobin from naïve males. Male LCHS/CS rats had reduced colony-forming units-granulocyte, -erythrocyte, -monocyte, -megakaryocyte (CFU-GEMM) and burst-forming unit-erythroid (BFU-E) when compared with female counterparts. Naïve, LCHS, and LCHS/CS males had lower serum iron than their respective female counterparts. Liver transcription of BMP4 and BMP6 was elevated after LCHS and LCHS/CS in males compared with females. The LCHS/CS males had decreased expression of bone marrow pro-erythroid factors compared with LCHS/CS females. After trauma with or without chronic stress, male rats demonstrated increased weight loss, substantial decrease in hemoglobin level, dysregulated iron metabolism, substantial suppression of bone marrow erythroid progenitor growth, and no change in transcription of pro-erythroid factors. These findings confirm that gender is an important variable that impacts anemia recovery and bone marrow dysfunction after traumatic injury and shock in this rat model.
10.1089/sur.2023.154
Effect of ferric ions on Cronobacter sakazakii growth, biofilm formation, and swarming motility.
International journal of food microbiology
Cronobacter sakazakii (C. sakazakii) is a common food-borne pathogen that induces meningitis, sepsis, and necrotizing enterocolitis, primarily in newborns and infants. Iron plays a pivotal role in the growth of cells and biofilm formation. However, the effects of hemin (ferric ion donor) on C. sakazakii cells are scarcely known. Here, we explored the effect of ferric ions on the growth of planktonic C. sakazakii, biofilm formation, and swarming motility by crystal violet staining (CVS), scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and swarming assay. Our study demonstrated that ferric ions facilitated the growth of planktonic C. sakazakii, while hemin at concentrations ranging from 50 to 800 μmol/L promoted biofilm formation and at concentrations between 50 and 200 μmol/L enhanced the swarming motility of C. sakazakii. Furthermore, high hemin concentrations (400-800 μmol/L) were found to reduce flagellar length, as confirmed by transmission electron microscopy (TEM). These findings indicated that ferric ions mediated the swarming motility of C. sakazakii by regulating flagellar assembly. Finally, transcriptomic analysis of C. sakazakii was performed at hemin concentrations of 0, 50, and 200 μmol/L, which revealed that several genes associated with iron transport and metabolism, and flagellar assembly were essential for the survival of C. sakazakii under hemin treatment. Our findings revealed the molecular basis of ferric ions on C. sakazakii growth and biofilm formation, thus providing a novel perspective for its prevention and control.
10.1016/j.ijfoodmicro.2023.110418
Protective response against with ferric iron receptors HemTR-BauA in a murine sepsis model.
Ramezanalizadeh Fatemeh,Rasooli Iraj,Owlia Parviz
Future microbiology
Iron uptake and metabolism pathways are promising targets in vaccine development as an alternative strategy for antibiotics. HemTR, a putative heme receptor of , was expressed and its protectivity against was determined singly or in combination with the siderophore receptor, BauA, in mice. High level of IgG was elicited. There was a delay in mice mortality with reduced bacterial loads in internal organs in the sublethal challenge. Protection was better in the HemTR-BauA group in both lethal and sublethal challenges. Passive transfer of anti-HemTR and anti-BauA partially protected mice against infection. HemTR in combination with other iron receptors could contribute to the development of protective vaccines against .
10.2217/fmb-2020-0133
Platelets accelerate lipid peroxidation and induce pathogenic neutrophil extracellular trap release.
Cell chemical biology
Neutrophil extracellular traps (NETs), an important host defense mechanism, are assembled after the release of decondensed chromatin and other nuclear components by a process termed NETosis. However, excessive NET release destroys surrounding tissues, leading to conditions such as sepsis where platelets are implicated in the pathogenic switch of NETosis. Here, we show that platelets trigger iron accumulation and promote lipid peroxide production in neutrophils co-stimulated with lipopolysaccharide and platelets in vitro, resulting in the induction of NETosis. We also screened for compounds that inhibit lipid peroxidation, identified 8-methyl-N-geranyl-6-nonamide (capsaicin), and assessed its potential in suppressing platelet-mediated pathogenic NETosis. Capsaicin inhibited lipopolysaccharide/platelet-induced cellular lipid peroxidation and suppressed NETosis in vitro. Furthermore, capsaicin attenuated NETosis in a mouse model of lipopolysaccharide-induced lung inflammation. Our findings provide an original therapeutic strategy to target lipid peroxidation and pave the way for drug development for a wide range of NETosis-related diseases.
10.1016/j.chembiol.2024.11.003
Anaemia and transfusion triggers in critically ill patients - What we have learnt thus far.
Jandu Amritpal Singh,Vidgeon Steven,Ahmed Nadeem
Journal of the Intensive Care Society
Anaemia is a common finding in critically ill patients, the cause of which is multi-factorial including: sepsis, haemolysis (and disseminated intravascular coagulation), iatrogenic blood loss secondary to laboratory sampling, post-operative anaemia, bone marrow suppression/failure, decreased production of erythropoietin, anaemia secondary to drugs/toxins, overt or occult blood loss, functional iron deficiency, poor nutrition and haemodilution. Anaemia is associated with deleterious outcomes including increased risk of cardiac-related morbidity and mortality and decrease in oxygen-carrying capacity in the face of increased metabolic demands. There is a growing body of evidence, which demonstrates that packed red blood cell transfusions are associated with poorer outcomes. Clinicians therefore need to weigh the potential benefit of treating anaemia against the desire to avoid unnecessary transfusions. We explored current literature regarding transfusion triggers and morbidity and mortality associated with packed red blood cell transfusions transfusion, concentrating on studies that have been conducted in critical care patients. In addition, we reflected on trials which considered the viability of iron transfusion and erythropoietin in critically unwell patients.
10.1177/1751143718783615
Prediction of Poor Outcomes for Septic Children According to Ferritin Levels in a Middle-Income Setting.
Tonial Cristian T,Costa Caroline A D,Andrades Gabriela R H,Crestani Francielly,Einloft Paulo R,Bruno Francisco,Miranda Ana P,Fiori Humberto H,Garcia Pedro Celiny R
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
OBJECTIVES:To evaluate serum ferritin measured within 48 hours of admission as a prognostic marker and examine the association with unfavorable outcomes in a population of pediatric patients with sepsis and high prevalence of iron deficiency anemia in which this biomarker is routinely measured. DESIGN:Retrospective cohort study. SETTING:PICU of a tertiary care teaching hospital in a middle-income country in South America. PATIENTS:All patients 6 months to 18 years old (n = 350) admitted with a diagnosis of sepsis, suspected or proven, were eligible for inclusion. Exclusion criteria were length of PICU stay less than 8 hours and inherited or acquired disorder of iron metabolism that could interfere with serum ferritin levels. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Three-hundred twelve patients had their ferritin levels measured within 48 hours, and only 38 did not. The prevalence of iron deficiency anemia (hemoglobin < 11 g/dL and mean corpuscular volume < 80 fl was 40.3%. The median of the highest serum ferritin level within 48 hours was 150.5 ng/mL (interquartile range, 82.25-362 ng/mL), being associated with mortality (p < 0.001; Exp(B), 5.170; 95% CI, 2.619-10.205). A 10-fold increase in ferritin level was associated with a five-fold increase in mortality. There was a monotonic increase in mortality with increasing ferritin levels (p < 0.05). Regarding the discriminatory power of ferritin for mortality, the area under the receiver operating characteristic curve was 0.787 (95% CI, 0.737-0.83; p < 0.0001). CONCLUSIONS:Serum ferritin at lower thresholds predicts mortality in children with sepsis admitted to the ICU in a middle-income country with high prevalence of iron deficiency anemia.
10.1097/PCC.0000000000002273
Zinc Protoporphyrin-to-Heme Ratio and Ferritin as Measures of Iron Sufficiency in the Neonatal Intensive Care Unit.
German Kendell,Vu Phuong T,Grelli Kimberly N,Denton Christopher,Lee Gina,Juul Sandra E
The Journal of pediatrics
OBJECTIVES:To evaluate ferritin and zinc protoporphyrin-to-heme (ZnPP/H) ratios as biomarkers of iron status in neonates, determine how specific clinical events affected these measures, and assess how iron status changed during hospitalization. STUDY DESIGN:We performed a retrospective study of all infants with paired ferritin and ZnPP/H measurements between October 2014 and May 2016. Concordance of these measurements, effects of sepsis, red blood cell transfusion, erythropoietin treatment, and iron supplementation were assessed. Iron status was measured over time. RESULTS:A total of 228 patients (mean birth weight 1.3 kg, median gestational age 29 weeks) were evaluated. Mean log ZnPP/H values in infants with and without sepsis were not significantly different (4.98 µmol/mol vs 4.97 µmol/mol, adjusted P = .103), whereas log-transformed ferritin values increased significantly during infection (5.23 ng/mL vs 4.04 ng/mL, adjusted P < .001). Ferritin also increased more significantly than ZnPP/H following red blood cell transfusion (ferritin: mean 5.03 ng/mL vs 4.0 ng/mL, P < .001; ZnPP/H: mean 4.85 µmol/mol vs 4.98 µmol/mol, P < .001). The mean iron supplementations at 30, 60, and 90 days were 5.4, 6.9, and 7.4 mg/kg/day, respectively. Ferritin values decreased with advancing postnatal age (adjusted P < .001), with 66% of ferritin values less than 76 ng/mL. Treatment with erythropoietin increased ZnPP/H, but not ferritin levels. CONCLUSIONS:Ferritin is more significantly affected by inflammatory events such as sepsis and transfusion than ZnPP/H, thus, ZnPP/H may be a more reliable marker of iron status in this population. Infants showed worsening iron sufficiency over time despite supplementation above American Academy of Pediatrics guidelines.
10.1016/j.jpeds.2017.10.041
Scavenging of bacteria or bacterial products by magnetic particles functionalized with a broad-spectrum pathogen recognition receptor motif offers diagnostic and therapeutic applications.
Acta biomaterialia
Sepsis is a dysregulated host response of severe bloodstream infections, and given its frequency of occurrence and high mortality rate, therapeutic improvements are imperative. A reliable biomimetic strategy for the targeting and separation of bacterial pathogens in bloodstream infections involves the use of the broad-spectrum binding motif of human GP-340, a pattern-recognition receptor of the scavenger receptor cysteine rich (SRCR) superfamily that is expressed on epithelial surfaces but not found in blood. Here we show that these peptides, when conjugated to superparamagnetic iron oxide nanoparticles (SPIONs), can separate various bacterial endotoxins and intact microbes (E. coli, S. aureus, P. aeruginosa and S. marcescens) with high efficiency, especially at low and thus clinically relevant concentrations. This is accompanied by a subsequent strong depletion in cytokine release (TNF, IL-6, IL-1β, Il-10 and IFN-γ), which could have a direct therapeutic impact since escalating immune responses complicates severe bloodstream infections and sepsis courses. SPIONs are coated with aminoalkylsilane and capture peptides are orthogonally ligated to this surface. The particles behave fully cyto- and hemocompatible and do not interfere with host structures. Thus, this approach additionally aims to dramatically reduce diagnostic times for patients with suspected bloodstream infections and accelerate targeted antibiotic therapy. STATEMENT OF SIGNIFICANCE: Sepsis is often associated with excessive release of cytokines. This aspect and slow diagnostic procedures are the major therapeutic obstacles. The use of magnetic particles conjugated with small peptides derived from the binding motif of a broad-spectrum mucosal pathogen recognition protein GP-340 provides a highly efficient scavenging platform. These peptides are not found in blood and therefore are not subject to inhibitory mechanisms like in other concepts (mannose binding lectine, aptamers, antibodies). In this work, data are shown on the broad bacterial binding spectrum, highly efficient toxin depletion, which directly reduces the release of cytokines. Host cells are not affected and antibiotics not adsorbed. The particle bound microbes can be recultured without restriction and thus be used directly for diagnostics.
10.1016/j.actbio.2022.01.001
Ferritin Light Chain Confers Protection Against Sepsis-Induced Inflammation and Organ Injury.
Frontiers in immunology
Despite the prevalence and recognition of its detrimental impact, clinical complications of sepsis remain a major challenge. Here, we investigated the effects of myeloid ferritin heavy chain (FtH) in regulating the pathogenic sequelae of sepsis. We demonstrate that deletion of myeloid FtH leads to protection against lipopolysaccharide-induced endotoxemia and cecal ligation and puncture (CLP)-induced model of sepsis as evidenced by reduced cytokine levels, multi-organ dysfunction and mortality. We identified that such protection is predominantly mediated by the compensatory increase in circulating ferritin (ferritin light chain; FtL) in the absence of myeloid FtH. Our and studies indicate that prior exposure to ferritin light chain restrains an otherwise dysregulated response to infection. These findings are mediated by an inhibitory action of FtL on NF-κB activation, a key signaling pathway that is implicated in the pathogenesis of sepsis. We further identified that LPS mediated activation of MAPK pathways, specifically, JNK, and ERK were also reduced with FtL pre-treatment. Taken together, our findings elucidate a crucial immunomodulatory function for circulating ferritin that challenges the traditional view of this protein as a mere marker of body iron stores. Accordingly, these findings will stimulate investigations to the adaptive nature of this protein in diverse clinical settings.
10.3389/fimmu.2019.00131
Persistent inflammation and anemia among critically ill septic patients.
Loftus Tyler J,Mira Juan C,Stortz Julie A,Ozrazgat-Baslanti Tezcan,Ghita Gabriella L,Wang Zhongkai,Brumback Babette A,Ungaro Ricardo F,Bihorac Azra,Leeuwenburgh Christiaan,Moore Frederick A,Moldawer Lyle L,Brakenridge Scott C,Efron Philip A,Mohr Alicia M
The journal of trauma and acute care surgery
BACKGROUND:Associations among inflammatory cytokines, erythropoietin (EPO), and anemia in critically ill septic patients remain unclear. This study tested the hypothesis that elevated inflammatory cytokines and decreased EPO would be associated with iron-restricted anemia while accounting for operative blood loss, phlebotomy blood loss, and red blood cell (RBC) transfusion volume. METHODS:Prospective observational cohort study of 42 critically ill septic patients was conducted. Hemoglobin (Hb) at sepsis onset and hospital discharge were used to calculate ΔHb. Operative blood loss, phlebotomy blood loss, and RBC transfusion volume were used to calculate adjusted ΔHb (AdjΔHb) assuming that 300 mL RBC is equal to 1 g/dL Hb. Patients with AdjΔHb of greater than 0 (positive AdjΔHb, n = 18) were compared with patients with AdjΔHb of less than or equal to 0 (negative AdjΔHb, n = 24). RESULTS:Plasma tumor necrosis factor α, granulocyte colony-stimulating factor, interleukin (IL)-6, IL-8, EPO, erythrocyte mean corpuscular volume, and serum transferrin receptor were measured on days 0, 1, 4, 7, and 14. Patients with negative AdjΔHb had significantly higher day 14 levels of IL-6 (37.4 vs. 15.2 pg/mL, p < 0.05), IL-8 (39.1 vs. 18.2 pg/mL, p = 0.01), and granulocyte colony-stimulating factor (101.3 vs. 60.5 pg/mL, p = 0.01), but not EPO. On linear regression analysis, lower AdjΔHb was associated with higher day 14 levels of IL-6 (r = 0.22, p < 0.01), IL-8 (r = 0.10, p = 0.04), stromal cell-derived factor 1 (r = 0.14, p = 0.02), and tumor necrosis factor α (r = 0.13, p = 0.02), but not EPO. Patients with negative AdjΔHb had significantly lower mean corpuscular volume on days 4 (89.6 vs. 93.2 fL/cell, p = 0.04), 7 (92.3 vs. 94.9 fL/cell, p = 0.04), and 14 (92.1 vs. 96.0 fL/cell, p = 0.03) but similar serum transferrin receptor levels. CONCLUSION:Persistent elevation of inflammatory cytokines was associated with iron-restricted anemia among critically ill septic patients, occurring in the absence of systemic iron deficiency, independent of endogenous EPO. LEVEL OF EVIDENCE:Prognostic study, level II.
10.1097/TA.0000000000002147
Exploring the Antibacterial Activity and Cellular Fates of Enterobactin-Drug Conjugates That Target Gram-Negative Bacterial Pathogens.
Accounts of chemical research
Siderophores are secondary metabolites utilized by bacteria to acquire iron (Fe), an essential transition metal nutrient. Fe levels in the host environment are tightly regulated and can be further restricted to starve invading bacterial pathogens in a host-defense process known as nutritional immunity. To survive and colonize the Fe-limited host environment, bacteria produce siderophores and express cognate siderophore transport machinery. These active transport pathways present an opportunity for selective and efficient drug delivery into bacterial cells, motivating decades of research on synthetic siderophore-antibiotic conjugates (SACs) as a Trojan-horse strategy for the development of targeted antibiotics.Enterobactin (Ent) is a triscatecholate siderophore produced and utilized by many Gram-negative bacteria, including all and species. Within these species, pathogenic strains cause a variety of human diseases including urinary tract infections, gastroenteritis, and sepsis. Infections caused by these Gram-negative pathogens can be difficult to treat because of the impermeability of the outer membrane (OM). This impermeability can be overcome by utilizing siderophores as drug delivery vectors for targeting Gram-negative pathogens. Ent is a promising delivery vector because it undergoes active transport across the OM mediated by the Ent uptake machinery after scavenging Fe(III) from the extracellular environment. Despite the well-elucidated chemistry and biology of Ent, its use for SAC development was hampered by the lack of an appropriate functional group for cargo attachment. Our laboratory addressed this need by designing and synthesizing monofunctionalized Ent scaffolds. Over the past decade, we have used these scaffolds to explore Ent-based SACs with a variety of drug warheads, including β-lactam and fluoroquinolone antibiotics, and Pt(IV) prodrugs. Investigations of the antibacterial activities of these conjugates and their cellular fates have informed our design principles and revealed approaches to achieving enhanced antibacterial potency and pathogen-targeted activity. Collectively, our studies of Ent-drug conjugates have provided discoveries, understanding, and invaluable insights for future design and evaluation of SACs.In this Account, we present the story of our work on Ent-drug conjugates that began about ten years ago with the development of monofunctionalized Ent scaffolds and the design and synthesis of various conjugates based on these scaffolds. We describe the antibacterial activity profiles and uptake pathways of Ent-drug conjugates harboring traditional antibiotics and repurposed platinum anticancer agents as well as studies that address cellular targets and fates. Finally, we discuss other applications of monofunctionalized Ent scaffolds, including a siderophore-based immunization strategy. We intend for this Account to inspire further investigations into the fundamental understanding and translational applications of siderophores and siderophore-drug conjugates.
10.1021/acs.accounts.3c00814
Major role of iron uptake systems in the intrinsic extra-intestinal virulence of the genus Escherichia revealed by a genome-wide association study.
Galardini Marco,Clermont Olivier,Baron Alexandra,Busby Bede,Dion Sara,Schubert Sören,Beltrao Pedro,Denamur Erick
PLoS genetics
The genus Escherichia is composed of several species and cryptic clades, including E. coli, which behaves as a vertebrate gut commensal, but also as an opportunistic pathogen involved in both diarrheic and extra-intestinal diseases. To characterize the genetic determinants of extra-intestinal virulence within the genus, we carried out an unbiased genome-wide association study (GWAS) on 370 commensal, pathogenic and environmental strains representative of the Escherichia genus phylogenetic diversity and including E. albertii (n = 7), E. fergusonii (n = 5), Escherichia clades (n = 32) and E. coli (n = 326), tested in a mouse model of sepsis. We found that the presence of the high-pathogenicity island (HPI), a ~35 kbp gene island encoding the yersiniabactin siderophore, is highly associated with death in mice, surpassing other associated genetic factors also related to iron uptake, such as the aerobactin and the sitABCD operons. We confirmed the association in vivo by deleting key genes of the HPI in E. coli strains in two phylogenetic backgrounds. We then searched for correlations between virulence, iron capture systems and in vitro growth in a subset of E. coli strains (N = 186) previously phenotyped across growth conditions, including antibiotics and other chemical and physical stressors. We found that virulence and iron capture systems are positively correlated with growth in the presence of numerous antibiotics, probably due to co-selection of virulence and resistance. We also found negative correlations between virulence, iron uptake systems and growth in the presence of specific antibiotics (i.e. cefsulodin and tobramycin), which hints at potential "collateral sensitivities" associated with intrinsic virulence. This study points to the major role of iron capture systems in the extra-intestinal virulence of the genus Escherichia.
10.1371/journal.pgen.1009065
The effect of red blood cell transfusion on iron metabolism in critically ill patients.
Boshuizen Margit,van Hezel Maike E,van Manen Lisa,Straat Marleen,Somsen Yvemarie B O,Spoelstra-de Man Angelique M E,Blumberg Neil,van Bruggen Robin,Juffermans Nicole P
Transfusion
BACKGROUND:Anemia of inflammation (AI) has a high prevalence in critically ill patients. In AI, iron metabolism is altered, as high levels of inflammation-induced hepcidin reduce the amount of iron available for erythropoiesis. AI is treated with red blood cell (RBC) transfusions. The effect of RBC transfusion on iron metabolism during inflammatory processes in adults is unknown. We investigated the effect of RBC transfusion on iron metabolism in critically ill patients. METHODS:In a prospective cohort study in 61 critically ill patients who received 1 RBC unit, levels of iron variables were determined before, directly after, and 24 hours after transfusion in septic and nonseptic patients. RESULTS:Serum iron levels were low and increased after transfusion (p = 0.02). However, RBC transfusion had no effect on transferrin saturation (p = 0.14) and ferritin levels (p = 0.74). Hepcidin levels increased after RBC transfusion (p = 0.01), while interleukin-6 levels decreased (p = 0.03). In septic patients, RBC transfusion induced a decrease in haptoglobin levels compared to baseline, which did not occur in nonseptic patients (p = 0.01). The effect of RBC transfusion on other iron variables did not differ between septic and nonseptic patients. CONCLUSION:Transfusion of a RBC unit transiently increases serum iron levels in intensive care unit patients. The increase in hepcidin levels after transfusion can further decrease iron release from intracellular storage making it available for erythropoiesis. RBC transfusion is associated with a decrease in haptoglobin levels in septic compared to nonseptic patients, but did not affect other markers of hemolysis.
10.1111/trf.15127
Dopamine Is a Siderophore-Like Iron Chelator That Promotes Serovar Typhimurium Virulence in Mice.
Dichtl Stefanie,Demetz Egon,Haschka David,Tymoszuk Piotr,Petzer Verena,Nairz Manfred,Seifert Markus,Hoffmann Alexander,Brigo Natascha,Würzner Reinhard,Theurl Igor,Karlinsey Joyce E,Fang Ferric C,Weiss Günter
mBio
We have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course of infections. Dopamine was found to promote the growth of both in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected with serovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth. lacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria. Here we show that dopamine increases bacterial iron incorporation and promotes Typhimurium growth both and These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.
10.1128/mBio.02624-18
Hepcidin Protects against Lethal Escherichia coli Sepsis in Mice Inoculated with Isolates from Septic Patients.
Stefanova Deborah,Raychev Antoan,Deville Jaime,Humphries Romney,Campeau Shelley,Ruchala Piotr,Nemeth Elizabeta,Ganz Tomas,Bulut Yonca
Infection and immunity
Iron is an essential micronutrient for most microbes and their hosts. Mammalian hosts respond to infection by inducing the iron-regulatory hormone hepcidin, which causes iron sequestration and a rapid decrease in the plasma and extracellular iron concentration (hypoferremia). Previous studies showed that hepcidin regulation of iron is essential for protection from infection-associated mortality with the siderophilic pathogens and However, the evolutionary conservation of the hypoferremic response to infection suggests that not only rare siderophilic bacteria but also common pathogens may be targeted by this mechanism. We tested 10 clinical isolates of from children with sepsis and found that both genetic iron overload (by hepcidin-1 knockout [HKO]) and iatrogenic iron overload (by intravenous iron) potentiated infection with 8 out of the 10 studied isolates: after peritoneal injection of , iron-loaded mice developed sepsis with 60% to 100% mortality within 24 h, while control wild-type mice suffered 0% mortality. Using one strain for more detailed study, we show that iron overload allows rapid bacterial multiplication and dissemination. We further found that the presence of non-transferrin-bound iron (NTBI) in the circulation is more important than total plasma or tissue iron in rendering mice susceptible to infection and mortality. Postinfection treatment of HKO mice with just two doses of the hepcidin agonist PR73 abolished NTBI and completely prevented sepsis-associated mortality. We demonstrate that the siderophilic phenotype extends to clinically common pathogens. The use of hepcidin agonists promises to be an effective early intervention in patients with infections and dysregulated iron metabolism.
10.1128/IAI.00253-18
Linkage of alterations in systemic iron homeostasis to patients' outcome in sepsis: a prospective study.
Journal of intensive care
BACKGROUND:Sepsis, a dysregulated host response following infection, is associated with massive immune activation and high mortality rates. There is still a need to define further risk factors and laboratory parameters predicting the clinical course. Iron metabolism is regulated by both, the body's iron status and the immune response. Iron itself is required for erythropoiesis but also for many cellular and metabolic functions. Moreover, iron availability is a critical determinant in infections because it is an essential nutrient for most microbes but also impacts on immune function and intravascular oxidative stress. Herein, we used a prospective study design to investigate the putative impact of serum iron parameters on the outcome of sepsis. METHODS:Serum markers of iron metabolism were measured in a prospective cohort of 61 patients (37 males, 24 females) with sepsis defined by Sepsis-3 criteria in a medical intensive care unit (ICU) and compared between survivors and non-survivors. Regulation of iron parameters in patients stratified by focus of infection and co-medication as well as association of the markers with sepsis severity scores and survival were investigated with linear and logistic regression corrected for sex and age effects. RESULTS:Positive correlations of increased serum iron and ferritin concentrations upon ICU admission with the severity of organ failure (SOFA score) and with mortality were observed. Moreover, high TF-Sat, elevated ferritin and serum iron levels and low transferrin concentrations were associated with reduced survival. A logistic regression model consisting of SOFA and transferrin saturation (SOFA-TF-Sat) had the best predictive power for survival in septic ICU patients. Of note, administration of blood transfusions prior to ICU admission resulted in increased TF-Sat and reduced survival of septic patients. CONCLUSIONS:Our study could show an important impact of serum iron parameters on the outcome of sepsis. Furthermore, we identified transferrin saturation as a stand-alone predictor of sepsis survival and as a parameter of iron metabolism which may in a combined model improve the prediction power of the SOFA score. TRIAL REGISTRATION:The study was carried out in accordance with the recommendations of the Declaration of Helsinki on biomedical research. The study was approved by the institutional ethics review board of the Medical University Innsbruck (study AN2013-0006).
10.1186/s40560-020-00495-8
Crosstalk of pyroptosis, ferroptosis, and mitochondrial aldehyde dehydrogenase 2-related mechanisms in sepsis-induced lung injury in a mouse model.
Bioengineered
Acute lung injury (ALI) is a common complication of sepsis. Mitochondrial aldehyde dehydrogenase 2 (ALDH2), an enzyme involved in aldehyde metabolism, exerts a protective effect against sepsis. This study investigated the possible mechanisms underlying the roles of ALDH2, pyroptosis, and ferroptosis in sepsis-induced lung injury. A mouse model of sepsis-induced lung injury was established by cecal ligation and puncture (CLP); lung morphology was evaluated by calculation of lung coefficient, hematoxylin-eosin staining, and electron microscopy. Malondialdehyde (MDA), reactive oxygen species (ROS), and 4-hydroxy-2-nonenal (4-HNE) protein expression levels were used to detect the level of lipid oxidative stress. In addition, total iron was detected using an iron detection kit, and the expression of ferroptosis-related proteins (PTGS2, GPX4), pyroptosis-related proteins, and ALDH2 was examined using western blotting. To further examine the likely mechanisms, the ferroptosis inhibitor ferrostatin 1 (Fer-1), NLRP3 inflammasome inhibitor MCC950, and ALDH2 activator Alda-1 were added. CLP-treated mice exhibited destruction of lung tissue morphology, lipid peroxidation injury, iron content, and increased lung PTGS2 protein expression, accompanied by a decrease in GPX4 protein expression. CLP also downregulated ALDH2 expression and increased the expression of the NLRP3 inflammasome and pyroptosis-related proteins. These adverse effects of CLP were relieved by Alda-1, Fer-1, and MCC950 treatment. In conclusion, both pyroptosis and ferroptosis participate in CLP-induced ALI, and ALDH2 plays a protective role by reducing pyroptosis and ferroptosis. This study provides a scientific basis for the treatment of lung injury in sepsis.
10.1080/21655979.2022.2033381
Predictors of Blood Culture Positivity in Pediatric Brucellosis.
Kara Soner Sertan,Cayir Yasemin
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP
OBJECTIVE:To investigate the predictors of blood culture positivity in children with brucellosis. STUDY DESIGN:Descriptive study. PLACE AND DURATION OF STUDY:Department of Pediatric Infectious Diseases in Erzurum Regional Training and Research Hospital, Turkey, from January to December 2015. METHODOLOGY:Eighty-six children under 16 years of age, with brucellosis, were retrospectively evaluated. Compatible clinical findings plus presence of positivity at titers of >1:160 in serum and/or Coombs agglutination tests in a single serum sample and/or a minimum fourfold increase within a 2-3 week interval were diagnostic for brucellosis. Only patients with blood cultures were included. Patients' demographical, clinical, and laboratory risk factors, such as age, gender, presence and duration of symptoms, and laboratory characteristics were analysed. RESULTS:Brucella spp. grew in blood cultures of 24 (27.9%) patients. Children with blood culture positivity had shorter symptom duration than those with negative blood cultures (p=0.03). Absence of personal and household histories of brucellosis (p=0.02 and p=0.04, respectively), lower hemoglobin, iron, and vitamin D (p<0.001, p=0.006, and p=0.006, respectively), and higher leukocyte, CRP, and ferritin (p<0.001, p=0.001, and p<0.001, respectively) levels were associated with isolation of Brucella spp. in blood culture. Children with positive blood cultures had higher serum tube and Coombs agglutination test results (p=0.001 and p<0.001). ROC analysis showed that ferritin at a cut-off level of 122 ng/mL (CI 95% 0.86-0.97, p<0.001) and Brucella Coombs agglutination test at a cut-off level of 1/480 (CI 95% 0.84-0.96, p<0.001) were the most sensitive and specific predictors of bacteremia. CONCLUSION:Serum hemoglobin, iron, ferritin, vitamin D, and C-reactive protein levels, Brucellar tube and Coombs agglutination tests, and leukocyte count could help to predict definitive diagnosis in pediatric brucellosis when molecular techniques are not feasible, such as in source-limited countries.
10.29271/jcpsp.2019.07.665
Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice.
Frontiers in cellular and infection microbiology
Introduction:Hepcidin is the systemic master regulator of iron metabolism as it degrades the cellular iron exporter ferroportin. In bacterial infections, hepcidin is upregulated to limit circulating iron for pathogens, thereby increasing iron retention in macrophages. This mechanism withholds iron from extracellular bacteria but could be of disadvantage in infections with intracellular bacteria. We aimed to understand the role of hepcidin in infections with intra- or extracellular bacteria using different hepcidin inhibitors. Methods:For the experiments LDN-193189 and oversulfated heparins were used, which interact with the BMP6-SMAD pathway thereby inhibiting hepcidin expression. We infected male C57BL/6N mice with either the intracellular bacterium Typhimurium or the extracellular bacterium and treated these mice with the different hepcidin inhibitors. Results:Both inhibitors effectively reduced hepcidin levels under steady state conditions and upon stimulation with the inflammatory signals interleukin-6 or lipopolysaccharide. The inhibitors also reduced hepcidin levels and increased circulating iron concentration in uninfected mice. However, both compounds failed to decrease liver- and circulating hepcidin levels in infected mice and did not affect ferroportin expression in the spleen or impact on serum iron levels. Accordingly, both BMP-SMAD signaling inhibitors did not influence bacterial numbers in different organs in the course of or S.Tm sepsis. Conclusion:These data indicate that targeting the BMP receptor or the BMP-SMAD pathway is not sufficient to suppress hepcidin expression in the course of infection with both intra- or extracellular bacteria. This suggests that upon pharmacological inhibition of the central SMAD-BMP pathways during infection, other signaling cascades are compensatorily induced to ensure sufficient hepcidin formation and iron restriction to circulating microbes.
10.3389/fcimb.2021.705087
The Postinjury Inflammatory State and the Bone Marrow Response to Anemia.
Loftus Tyler J,Mira Juan C,Miller Elizabeth S,Kannan Kolenkode B,Plazas Jessica M,Delitto Daniel,Stortz Julie A,Hagen Jennifer E,Parvataneni Hari K,Sadasivan Kalia K,Brakenridge Scott C,Moore Frederick A,Moldawer Lyle L,Efron Philip A,Mohr Alicia M
American journal of respiratory and critical care medicine
RATIONALE:The pathophysiology of persistent injury-associated anemia is incompletely understood, and human data are sparse. OBJECTIVES:To characterize persistent injury-associated anemia among critically ill trauma patients with the hypothesis that severe trauma would be associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, and decreased erythropoiesis. METHODS:A translational prospective observational cohort study comparing severely injured, blunt trauma patients who had operative fixation of a hip or femur fracture (n = 17) with elective hip repair patients (n = 22). Bone marrow and plasma obtained at the index operation were assessed for circulating catecholamines, systemic inflammation, erythropoietin, iron trafficking pathways, and erythroid progenitor growth. Bone marrow was also obtained from healthy donors from a commercial source (n = 8). MEASUREMENTS AND MAIN RESULTS:During admission, trauma patients had a median of 625 ml operative blood loss and 5 units of red blood cell transfusions, and Hb decreased from 10.5 to 9.3 g/dl. Compared with hip repair, trauma patients had higher median plasma norepinephrine (21.9 vs. 8.9 ng/ml) and hepcidin (56.3 vs. 12.2 ng/ml) concentrations (both P < 0.05). Bone marrow erythropoietin and erythropoietin receptor expression were significantly increased among patients undergoing hip repair (23% and 14% increases, respectively; both P < 0.05), but not in trauma patients (3% and 5% increases, respectively), compared with healthy control subjects. Trauma patients had lower bone marrow transferrin receptor expression than did hip repair patients (57% decrease; P < 0.05). Erythroid progenitor growth was decreased in trauma patients (39.0 colonies per plate; P < 0.05) compared with those with hip repair (57.0 colonies per plate; P < 0.05 compared with healthy control subjects) and healthy control subjects (66.5 colonies per plate). CONCLUSIONS:Severe blunt trauma was associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, erythroid progenitor growth suppression, and persistent injury-associated anemia. Clinical trial registered with www.clinicaltrials.gov (NCT 02577731).
10.1164/rccm.201712-2536OC
Myeloid-specific ferritin light chain deletion does not exacerbate sepsis-associated AKI.
American journal of physiology. Renal physiology
Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life-threatening sequelae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprising ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed that myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtL) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, although sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evidenced by a rise in serum creatinine and cystatin C and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy postsepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NF-κB or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, the loss of FtL did not influence sepsis pathogenesis. Hyperferritinemia in sepsis is often associated with a proinflammatory phenotype and poor prognosis. We previously showed the myeloid deletion of FtH results in a compensatory increase in FtL and is associated with reduced circulating cytokines and decreased rates of SA-AKI in animal sepsis models. Here, we show that myeloid deletion of FtL does not impact the severity of SA-AKI following CLP or LPS, suggesting that FtH plays the predominant role in propagating myeloid-induced proinflammatory pathways.
10.1152/ajprenal.00043.2024
Biochanin A-mediated anti-ferroptosis is associated with reduction of septic kidney injury.
Life sciences
AIMS:This study aimed to investigate the therapeutic potential of biochanin A in a sepsis associated- acute kidney injury (SA-AKI) mouse model induced by lipopolysaccharide (LPS). MAIN METHODS:Male BALB/C mice (n = 7 per group) were injected with biochanin A (40 mg/kg, i.p.) or ferrostatin-1 (5 mg/kg, i.p.) in the presence or absence of LPS (10 mg/kg, i.p.). Survival rates were monitored twice a day for up to 2 weeks. Morphologic and functional changes in kidney tissue were assessed by H&E staining and by analyzing of levels of blood-urea nitrogen (BUN) and creatinine (CR) in serum, respectively. Kidney epithelial cell death was analyzed by TUNEL staining, Prussian blue staining, iron quantification, lipid peroxide quantification, and glutathione quantification. Anti-ferroptosis mechanism of biochanin A was analyzed by RNA sequencing in mouse embryonic fibroblast cells. KEY FINDINGS:Biochanin A increased the survival rate of septic mice and inhibited the secretion of high mobility group box 1, an important inflammatory mediator in sepsis. Biochanin A inhibited LPS-induced kidney damage by suppressing dilatation and kidney tubular epithelial cell death. Furthermore, serum levels of BUN and CR were reduced in biochanin A-treated endotoxemic mice. Biochanin A inhibited the accumulation of iron and lipid peroxide and prevented glutathione depletion in the kidney tissue. Also, nine genes associated with the anti-ferroptosis effects of biochanin A were identified by RNA sequencing analysis. SIGNIFICANCE:The present study suggests that biochanin A is an effective inhibitor of ferroptosis, representing a potential treatment or prophylactic for sepsis-related disorders such as SA-AKI.
10.1016/j.lfs.2024.123124
Hepcidin, in contrast to heparin binding protein, does not portend acute kidney injury in patients with community acquired septic shock.
PloS one
BACKGROUND:Acute kidney injury (AKI) is a common and severe complication in patients treated at an Intensive Care Unit (ICU). The pathogenesis of AKI has been reported to involve hypoperfusion, diminished oxygenation, systemic inflammation, and damage by increased intracellular iron concentration. Hepcidin, a regulator of iron metabolism, has been shown to be associated with sepsis and septic shock, conditions that can result in AKI. Heparin binding protein (HBP) has been reported to be associated with sepsis and AKI. The aim of the present study was to compare serum hepcidin and heparin binding protein (HBP) levels in relation to AKI in patients admitted to the ICU. METHODS:One hundred and forty patients with community acquired illness admitted to the ICU within 24 hours after first arrival to the hospital were included in the study. Eighty five of these patients were diagnosed with sepsis and 55 with other severe non-septic conditions. Logistic and linear regression models were created to evaluate possible correlations between circulating hepcidin and heparin-binding protein (HBP), stage 2-3 AKI, peak serum creatinine levels, and the need for renal replacement therapy (RRT). RESULTS:During the 7-day study period, 52% of the 85 sepsis and 33% of the 55 non-sepsis patients had been diagnosed with AKI stage 2-3 already at inclusion. The need for RRT was 20% and 15%, respectively, in the groups. Hepcidin levels at admission were significantly higher in the sepsis group compared to the non-sepsis group but these levels did not significantly correlate to the development of stage 2-3 AKI in the sepsis group (p = 0.189) nor in the non-sepsis group (p = 0.910). No significant correlation between hepcidin and peak creatinine levels, nor with the need for RRT was observed. Stage 2-3 AKI correlated, as expected, significantly with HBP levels at admission in both groups (Odds Ratio 1.008 (CI 1.003-1.014, p = 0.005), the need for RRT, as well as with peak creatinine in septic patients. CONCLUSION:Initial serum hepcidin, and HBP levels in patients admitted to the ICU are biomarkers for septic shock but in contrast to HBP, hepcidin does not portend progression of disease into AKI or a later need for RRT. Since hepcidin is a key regulator of iron metabolism our present data do not support a decisive role of initial iron levels in the progression of septic shock into AKI.
10.1371/journal.pone.0299257
Therapeutic Potential of Heme Oxygenase-1 and Carbon Monoxide in Acute Organ Injury, Critical Illness, and Inflammatory Disorders.
Ryter Stefan W
Antioxidants (Basel, Switzerland)
Heme oxygenase-1 (HO-1) is an inducible stress protein that catalyzes the oxidative conversion of heme to carbon monoxide (CO), iron, and biliverdin (BV), the latter of which is converted to bilirubin (BR) by biliverdin reductase. HO-1 has been implicated as a cytoprotectant in various models of acute organ injury and disease (i.e., lung, kidney, heart, liver). Thus, HO-1 may serve as a general therapeutic target in inflammatory diseases. HO-1 may function as a pleiotropic modulator of inflammatory signaling, via the removal of heme, and generation of its enzymatic degradation-products. Iron release from HO activity may exert pro-inflammatory effects unless sequestered, whereas BV/BR have well-established antioxidant properties. CO, derived from HO activity, has been identified as an endogenous mediator that can influence mitochondrial function and/or cellular signal transduction programs which culminate in the regulation of apoptosis, cellular proliferation, and inflammation. Much research has focused on the application of low concentration CO, whether administered in gaseous form by inhalation, or via the use of CO-releasing molecules (CORMs), for therapeutic benefit in disease. The development of novel CORMs for their translational potential remains an active area of investigation. Evidence has accumulated for therapeutic effects of both CO and CORMs in diseases associated with critical care, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS), mechanical ventilation-induced lung injury, pneumonias, and sepsis. The therapeutic benefits of CO may extend to other diseases involving aberrant inflammatory processes such as transplant-associated ischemia/reperfusion injury and chronic graft rejection, and metabolic diseases. Current and planned clinical trials explore the therapeutic benefit of CO in ARDS and other lung diseases.
10.3390/antiox9111153
Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis.
Lehmann Christian,Aali Maral,Zhou Juan,Holbein Bruce
Life (Basel, Switzerland)
Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine-DFO; deferiprone-DFP; and deferasirox-DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis.
10.3390/life11010057
Ferritin Levels on Hospital Admission Predict Hypoxic-Ischemic Encephalopathy in Patients After Out-of-Hospital Cardiac Arrest: A Prospective Observational Single-Center Study.
Journal of intensive care medicine
AIM:Out-of-hospital cardiac arrest (OHCA) is a major health concern in Western societies. Poor outcome after OHCA is determined by the extent of hypoxic-ischemic encephalopathy (HIE). Dysregulation of iron metabolism has prognostic relevance in patients with ischemic stroke and sepsis. The aim of this study was to determine whether serum iron parameters help to estimate outcomes after OHCA. METHODS:In this prospective single-center study, 70 adult OHCA patients were analyzed. Serum ferritin, iron, transferrin (TRF), and TRF saturation (TRFS) were measured in blood samples drawn on day 0 (admission), day 2, day 4, and 6 months after the return of spontaneous circulation (ROSC). The association of 4 iron parameters with in-hospital mortality, neurological outcome (cerebral performance category [CPC]), and HIE was investigated by receiver operating characteristics and multivariate regression analyses. RESULTS:OHCA subjects displayed significantly increased serum ferritin levels on day 0 and lowered iron, TRF, and TRFS on days 2 and 4 after ROSC, as compared to concentrations measured at a 6-month follow-up. Iron parameters were not associated with in-hospital mortality or neurological outcomes according to the CPC. Ferritin on admission was an independent predictor of features of HIE on cranial computed tomography and death due to HIE. CONCLUSION:OHCA is associated with alterations in iron metabolism that persist for several days after ROSC. Ferritin on admission can help to predict HIE.
10.1177/08850666241252602
Suspecting Hyperferritinemic Sepsis in Iron-Deficient Population: Do We Need a Lower Plasma Ferritin Threshold?
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
OBJECTIVES:Hyperferritinemia is being suggested to identify patients with sepsis-induced macrophage activation syndrome for early intervention. However, data among iron-deficient children are scarce. This study was planned to explore the biological behavior of plasma ferritin in children from communities with a high frequency of iron deficiency with septic shock and its association with the outcome. DESIGN:Prospective observational study. SETTING:Tertiary care teaching hospital in a low-middle income economy of South Asia. PATIENTS OR SUBJECTS:Patients (6 mo to 12 yr) (n = 42) with septic shock and their healthy siblings as controls (n = 36). Patients/controls with blood transfusion/iron supplement during last 6 months or with any chronic disease were excluded. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Ferritin was measured in patients at enrollment and then at 1 month of hospital discharge while they were not on iron supplementation and in controls as indicative of baseline level. Patients' median age was 30 months (13.5-87 mo), 31% were malnourished, majority (86%) had anemia, and two thirds had microcytic hypochromic red cells. Ferritin at admission was 763 ng/mL (480-1,820 ng/mL) in nonsurvivors, whereas 415 ng/mL (262-852 ng/mL) in survivors (p = 0.11). Pediatric Logistic Organ Dysfunction score and C-reactive protein correlated positively with plasma ferritin (p = 0.03 and p = 0.01, respectively) at enrollment. Elevated ferritin of greater than 500 ng/mL (relative risk, 2.48; 95% CI, 0.95-6.43) and greater than 1,000 ng/mL (relative risk, 1.94; 95% CI, 0.94-4.02) were associated with higher mortality but not independently. Among survivors, the 1-month follow-up ferritin fell significantly to 97 ng/mL (16-118 ng/mL) (p = 0.001). However, it was still significantly higher than that in sibling controls (19 ng/mL [10-54 ng/mL]) (p = 0.003). CONCLUSIONS:Ferritin rises significantly in septic shock patients despite iron deficiency and seems to correlate with the severity of inflammation and organ dysfunction. Even a lower threshold (of 500 or 1,000 ng/mL) could predict higher mortality. It may suggest the need for redefining the plasma ferritin threshold for suspecting hyperferritinemic sepsis and sepsis-induced macrophage activation syndrome in these patients. Larger studies with frequent ferritin measurements are desirable to validate these initial observations.
10.1097/PCC.0000000000001584
High Serum Iron level is Associated with Increased Mortality in Patients with Sepsis.
Lan Peng,Pan Kong-Han,Wang Shuo-Jia,Shi Qiu-Cheng,Yu Yun-Xian,Fu Ying,Chen Yan,Jiang Yan,Hua Xiao-Ting,Zhou Jian-Cang,Yu Yun-Song
Scientific reports
Iron is an essential nutrient for bacterial survival and thus higher iron levels may precipitate bacterial infections. We investigated the association between the serum iron level and prognosis in patients with sepsis by using the single-centre Medical Information Mart for Intensive Care III (MIMIC-III) database. Sepsis patients with iron parameters measured on ICU admission were included and stratified according to quartiles of serum iron levels. A total of 1,891 patients diagnosed with sepsis according to the Sepsis-3 criteria were included in this study, 324 of whom were septic shock. After adjusting for confounding variables, higher iron quartile was associated with an increase in 90-day mortality in the Cox regression analysis. Moreover, a stepwise increase in the risk of 90-day mortality was observed as the quartiles of serum iron levels increased in the patients with sepsis. In conclusion, higher serum iron levels were independently associated with increased 90-day mortality in this large cohort of patients with sepsis.
10.1038/s41598-018-29353-2
Lactoferrin: A Critical Mediator of Both Host Immune Response and Antimicrobial Activity in Response to Streptococcal Infections.
ACS infectious diseases
Streptococcal species are Gram-positive bacteria responsible for a variety of disease outcomes including pneumonia, meningitis, endocarditis, erysipelas, necrotizing fasciitis, periodontitis, skin and soft tissue infections, chorioamnionitis, premature rupture of membranes, preterm birth, and neonatal sepsis. In response to streptococcal infections, the host innate immune system deploys a repertoire of antimicrobial and immune modulating molecules. One important molecule that is produced in response to streptococcal infections is lactoferrin. Lactoferrin has antimicrobial properties including the ability to bind iron with high affinity and sequester this important nutrient from an invading pathogen. Additionally, lactoferrin has the capacity to alter the host inflammatory response and contribute to disease outcome. This Review presents the most recent published work that studies the interaction between the host innate immune protein lactoferrin and the invading pathogen, .
10.1021/acsinfecdis.0c00050
The ferroportin Q248H mutation protects from anemia, but not malaria or bacteremia.
Science advances
Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the gene results in hemolytic anemia and increased fatality in malaria-infected mice. The Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth.
10.1126/sciadv.aaw0109
Labile heme impairs hepatic microcirculation and promotes hepatic injury.
Englert Franziska A,Seidel Raphael A,Galler Kerstin,Gouveia Zelia,Soares Miguel P,Neugebauer Ute,Clemens Mark G,Sponholz Christoph,Heinemann Stefan H,Pohnert Georg,Bauer Michael,Weis Sebastian
Archives of biochemistry and biophysics
Sepsis is a life-threatening clinical syndrome defined as a deregulated host response to infection associated with organ dysfunction. Mechanisms underlying the pathophysiology of septic liver dysfunction are incompletely understood. Among others, the iron containing tetrapyrrole heme inflicts hepatic damage when released into the circulation during systemic inflammation and sepsis. Accordingly, hemolysis and decreased concentrations of heme-scavenging proteins coincide with an unfavorable outcome of critically ill patients. As the liver is a key organ in heme metabolism and host response to infection, we investigated the impact of labile heme on sinusoidal microcirculation and hepatocellular integrity. We here provide experimental evidence that heme increases portal pressure via a mechanism that involves hepatic stellate cell-mediated sinusoidal constriction, a hallmark of microcirculatory failure under stress conditions. Moreover, heme exerts direct cytotoxicity in vitro and aggravates tissue damage in a model of polymicrobial sepsis. Heme binding by albumin, a low-affinity but high-capacity heme scavenger, attenuates heme-mediated vasoconstriction in vivo and prevents heme-mediated cytotoxicity in vitro. We demonstrate that fractions of serum albumin-bound labile heme are increased in septic patients. We propose that heme scavenging might be used therapeutically to maintain hepatic microcirculation and organ function in sepsis.
10.1016/j.abb.2019.108075
Iron metabolism in critically ill patients developing anemia of inflammation: a case control study.
Annals of intensive care
BACKGROUND:Anemia occurring as a result of inflammatory processes (anemia of inflammation, AI) has a high prevalence in critically ill patients. Knowledge on changes in iron metabolism during the course of AI is limited, hampering the development of strategies to counteract AI. This case control study aimed to investigate iron metabolism during the development of AI in critically ill patients. METHODS:Iron metabolism in 30 patients who developed AI during ICU stay was compared with 30 septic patients with a high Hb and 30 non-septic patients with a high Hb. Patients were matched on age and sex. Longitudinally collected plasma samples were analyzed for levels of parameters of iron metabolism. A linear mixed model was used to assess the predictive values of the parameters. RESULTS:In patients with AI, levels of iron, transferrin and transferrin saturation showed an early decrease compared to controls with a high Hb, already prior to the development of anemia. Ferritin, hepcidin and IL-6 levels were increased in AI compared to controls. During AI development, erythroferrone decreased. Differences in iron metabolism between groups were not influenced by APACHE IV score. CONCLUSIONS:The results show that in critically ill patients with AI, iron metabolism is already altered prior to the development of anemia. Levels of iron regulators in AI differ from septic controls with a high Hb, irrespective of disease severity. AI is characterized by high levels of hepcidin, ferritin and IL-6 and low levels of iron, transferrin and erythroferrone.
10.1186/s13613-018-0407-5
Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage.
Mertens Christina,Kuchler Laura,Sola Anna,Guiteras Roser,Grein Stephan,Brüne Bernhard,von Knethen Andreas,Jung Michaela
International journal of molecular sciences
During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls' staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.
10.3390/ijms21207527
Gut leakage enhances sepsis susceptibility in iron-overloaded β-thalassemia mice through macrophage hyperinflammatory responses.
Visitchanakun Peerapat,Saisorn Wilasinee,Wongphoom Jutamas,Chatthanathon Piraya,Somboonna Naraporn,Svasti Saovaros,Fucharoen Suthat,Leelahavanichkul Asada
American journal of physiology. Gastrointestinal and liver physiology
Iron overload induces intestinal-permeability defect (gut leakage), and gut translocation of organismal molecules might enhance systemic inflammation and sepsis severity in patients with thalassemia (Thal). Hence, iron administration in Hbb mice, heterozygous β-globin-deficient Thal mice, was explored. Oral iron administration induced more severe secondary hemochromatosis and gut leakage in Thal mice compared with wild-type (WT) mice. Gut leakage was determined by ) FITC-dextran assay, ) spontaneous serum elevation of endotoxin (LPS) and (1→3)-β-d-glucan (BG), molecular structures of gut-organisms, and ) reduction of tight-junction molecules with increased enterocyte apoptosis (activated caspase-3) by immunofluorescent staining. Iron overload also enhanced serum cytokines and increased spp. (gram-negative bacteria) in feces as analyzed by microbiome analysis. LPS injection in iron-overloaded Thal mice produced higher mortality and prominent cytokine responses. Additionally, stimulation with LPS plus iron in macrophage from Thal mice induced higher cytokines production with lower β-globin gene expression compared with WT. Furthermore, possible gut leakage as determined by elevated LPS or BG (>60 pg/mL) in serum without systemic infection was demonstrated in 18 out of 41 patients with β-thalassemia major. Finally, enhanced LPS-induced cytokine responses of mononuclear cells from these patients compared with cells from healthy volunteers were demonstrated. In conclusion, oral iron administration in Thal mice induced more severe gut leakage and increased fecal gram-negative bacteria, resulting in higher levels of endotoxemia and serum inflammatory cytokines compared with WT. Preexisting hyperinflammatory cytokines in iron-overloaded Thal enhanced susceptibility toward infection. Although the impact of iron accumulation in several organs of patients with thalassemia is well known, the adverse effect of iron accumulation in gut is not frequently mentioned. Here, we demonstrated iron-induced gut-permeability defect, impact of organismal molecules from gut translocation of, and macrophage functional defect upon the increased sepsis susceptibility in thalassemia mice.
10.1152/ajpgi.00337.2019
Causal Effects of Genetically Predicted Iron Status on Sepsis: A Two-Sample Bidirectional Mendelian Randomization Study.
Hu Yuanlong,Cheng Xiaomeng,Mao Huaiyu,Chen Xianhai,Cui Yue,Qiu Zhanjun
Frontiers in nutrition
Several observational studies showed a significant association between elevated iron status biomarkers levels and sepsis with the unclear direction of causality. A two-sample bidirectional mendelian randomization (MR) study was designed to identify the causal direction between seven iron status traits and sepsis. Seven iron status traits were studied, including serum iron, ferritin, transferrin saturation, transferrin, hemoglobin, erythrocyte count, and reticulocyte count. MR analysis was first performed to estimate the causal effect of iron status on the risk of sepsis and then performed in the opposite direction. The multiplicative random-effects and fixed-effects inverse-variance weighted, weighted median-based method and MR-Egger were applied. MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran's statistic methods were used to assess heterogeneity and pleiotropy. Genetically predicted high levels of serum iron (OR = 1.21, 95%CI = 1.13-1.29, = 3.16 × 10), ferritin (OR = 1.32, 95%CI = 1.07-1.62, =0.009) and transferrin saturation (OR = 1.14, 95%CI = 1.06-1.23, = 5.43 × 10) were associated with an increased risk of sepsis. No significant causal relationships between sepsis and other four iron status biomarkers were observed. This present bidirectional MR analysis suggested the causal association of the high iron status with sepsis susceptibility, while the reverse causality hypothesis did not hold. The levels of transferrin, hemoglobin, erythrocytes, and reticulocytes were not significantly associated with sepsis. Further studies will be required to confirm the potential clinical value of such a prevention and treatment strategy.
10.3389/fnut.2021.747547
ANXA1sp Protects against Sepsis-Induced Myocardial Injury by Inhibiting Ferroptosis-Induced Cardiomyocyte Death via SIRT3-Mediated p53 Deacetylation.
Mediators of inflammation
Sepsis-induced myocardial injury (SIMI), a common complication of sepsis, may cause significant mortality. Ferroptosis, a cell death associated with oxidative stress and inflammation, has been identified to be involved in SIMI. This study sought to investigate the role of ANXA1 small peptide (ANXA1sp) in SIMI pathogenesis. In this study, the mouse cardiomyocytes (H9C2 cells) were stimulated with lipopolysaccharide (LPS) to imitate SIMI . It was shown that ANXA1sp treatment substantially abated LPS-triggered H9C2 cell death and excessive secretion of proinflammatory cytokines (TNF-, IL-1, and IL-6). ANXA1sp pretreatment also reversed the increase of ROS and MDA generation as well as the decrease of SOD and GSH activity in H9C2 cells caused by LPS treatment. In addition, ANXA1sp considerably eliminated LPS-caused H9C2 cell ferroptosis, as revealed by the suppression of iron accumulation and the increase in GPX4 and FTH1 expression. Furthermore, the ameliorative effects of ANXA1sp on LPS-induced H9C2 cell damage could be partially abolished by erastin, a ferroptosis agonist. ANXA1sp enhanced SIRT3 expression in LPS-challenged H9C2 cells, thereby promoting p53 deacetylation. SIRT3 knockdown diminished ANXA1sp-mediated alleviation of cell death, inflammation, oxidative stress, and ferroptosis of LPS-treated H9C2 cells. Our study demonstrated that ANXA1sp is protected against LPS-induced cardiomyocyte damage by inhibiting ferroptosis-induced cell death via SIRT3-dependent p53 deacetylation, suggesting that ANXA1sp may be a potent therapeutic agent for SIMI.
10.1155/2023/6638929
Ferritin regulates organismal energy balance and thermogenesis.
Blankenhaus Birte,Braza Faouzi,Martins Rui,Bastos-Amador Patricia,González-García Ismael,Carlos Ana Rita,Mahu Inês,Faisca Pedro,Nunes Jose Moura,Ventura Pedro,Hoerr Verena,Weis Sebastian,Guerra Joel,Cardoso Silvia,Domingos Ana,López Miguel,Soares Miguel P
Molecular metabolism
OBJECTIVE:The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, which plays a central role in the regulation of cellular Fe metabolism. Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in a manner that impacts energy balance and thermal homeostasis. METHODS:We developed a mouse strain, referred herein as Fth, expressing a tamoxifen-inducible Cre recombinase under the control of the Rosa26 (R26) promoter and carrying two LoxP (fl) sites: one at the 5'end of the Fth promoter and another the 3' end of the first Fth exon. Tamoxifen administration induces global deletion of Fth in adult Fth mice, testing whether FTH is required for maintenance of organismal homeostasis. RESULTS:Under standard nutritional Fe supply, Fth deletion in adult Fth mice led to a profound deregulation of organismal Fe metabolism, oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly, Fth deletion was also associated with a profound atrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanistically to mitochondrial dysfunction, as assessed in the liver and in adipose tissue. CONCLUSION:The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismal redox homeostasis, energy expenditure and thermoregulation.
10.1016/j.molmet.2019.03.008
The possible mechanisms of ferroptosis in sepsis-associated acquired weakness.
Frontiers in physiology
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and its morbidity and mortality rates are increasing annually. It is an independent risk factor for intensive care unit-acquired weakness (ICU-AW), which is a common complication of patients in ICU. This situation is also known as sepsis-associated acquired weakness (SAW), and it can be a complication in more than 60% of patients with sepsis. The outcomes of SAW are often prolonged mechanical ventilation, extended hospital stays, and increased morbidity and mortality of patients in ICUs. The pathogenesis of SAW is unclear, and an effective clinical treatment is not available. Ferroptosis is an iron-dependent type of cell death with unique morphological, biochemical, and genetic features. Unlike other forms of cell death such as autophagy, apoptosis, and necrosis, ferroptosis is primarily driven by lipid peroxidation. Cells undergo ferroptosis during sepsis, which further enhances the inflammatory response. This process leads to increased cell death, as well as multi-organ dysfunction and failure. Recently, there have been sporadic reports suggesting that SAW is associated with ferroptosis, but the exact pathophysiological mechanisms remain unclear. Therefore, we reviewed the possible pathogenesis of ferroptosis that leads to SAW and offer new strategies to prevent and treat SAW.
10.3389/fphys.2024.1380992
Value of serum iron and urine neutrophil gelatinase-associated lipocalin in predicting the mortality of critically ill patients with sepsis.
Clinical and investigative medicine. Medecine clinique et experimentale
INTRODUCTION:We aimed to investigate the association of iron metabolism-related parameters with 60-day mortality in critically ill patients with sepsis. METHODS:Serum or urine concentrations of iron metabolism-related parameters on intensive care unit admission were measured in a prospective cohort of 133 eligible patients with sepsis according to the Sepsis-3 criteria, and these values were compared between survivors and nonsurvivors, categorized according to their 60-day survival status. Cox regression analyses were performed to examine the association between iron parameters and 60-day mortality. Kaplan-Meier methods were used to illustrate the differences in survival between different iron parameters. RESULTS:Of the 133 patients included in the study, 61 (45.8%) had died by day 60. After adjusting for confounding variables, higher concentrations of serum iron (cut-off 9.5 μmol/mL) and higher concentrations of urine neutrophil gelatinase-associated lipocalin (uNGAL; cut-off 169.3 ng/mL) were associated with a significantly greater risk of death in the Cox regression analysis. These two biomarkers combined with Sequential Organ Failure Assessment (SOFA) scores increased the area under the receiver operating characteristic (AUROC) curve to 0.85. DISCUSSION:These findings suggest that higher concentrations of serum iron and uNGAL are each associated with higher 60-day mortality, and they add significant accuracy to this prediction in combination with SOFA. uNGAL: urine neutrophil gelatinase-associated lipocalin; ICU: intensive care unit; SOFA: Sequential Organ Failure Assessment; APACHE II: the Acute Physiology and Chronic Health Evaluation II; ELISA: enzyme-linked immunosorbent assay; HR: hazard ratio; CIs: confidence intervals; WBC: white blood cell; TBIL: total bilirubin.
10.3138/cim-2024-2672
Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation.
JCI insight
Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+Fthfl/fl mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre+/+Fth+/+ and LysM-Cre+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1β pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.
10.1172/jci.insight.141760
FAM96A knock-out promotes alternative macrophage polarization and protects mice against sepsis.
Clinical and experimental immunology
Sepsis is an intractable clinical syndrome characterized by organ dysfunction when the body over-responds to an infection. Sepsis has a high fatality rate and lacks effective treatment. Family with sequence similarity 96 member A (FAM96A) is an evolutionarily conserved protein with high expression in the immune system and is related to cytosolic iron assembly and tumour suppression; however, research has been rarely conducted on its immune functions. Our study found that Fam96a mice significantly resisted lesions during sepsis simulated by caecal ligation and puncture (CLP) or endotoxicosis models. After a challenge with lipopolysaccharide (LPS) or infection, Fam96a mice exhibited less organ damage, longer survival and better bacterial clearance with decreased levels of proinflammatory cytokines. While screening several subsets of immune cells, FAM96A-expressing macrophages as the key cell type inhibited sepsis development. In-vivo macrophage depletion or adoptive transfer experiments abrogated significant differences in the survival of sepsis between Fam96a and wild-type mice. Results of the bone marrow-derived macrophage (BMDM) polarization experiment indicated that FAM96A deficiency promotes the transformation of uncommitted monocytes/macrophages (M0) into M2 macrophages, secreting fewer proinflammatory cytokines. FAM96A may mediate an immunometabolism shift - from oxidative phosphorylation (OXPHOS) to glycolysis - in macrophages during sepsis, mirrored by reactive oxygen species (ROS) and glucose uptake. These data demonstrate that FAM96A regulates inflammatory response and provide a novel genomic insight for sepsis treatment.
10.1111/cei.13555
Conserved metabolic regulator ArcA responds to oxygen availability, iron limitation, and cell envelope perturbations during bacteremia.
mBio
IMPORTANCE:Infections of the bloodstream are life-threatening and can result in sepsis. Gram-negative bacteria cause a significant portion of bloodstream infections, which is also referred to as bacteremia. The long-term goal of our work is to understand how such bacteria establish and maintain infection during bacteremia. We have previously identified the transcription factor ArcA, which promotes fermentation in bacteria, as a likely contributor to the growth and survival of bacteria in this environment. Here, we study ArcA in the Gram-negative species , and . Our findings aid in determining how these bacteria sense their environment, utilize nutrients, and generate energy while countering the host immune system. This information is critical for developing better models of infection to inform future therapeutic development.
10.1128/mbio.01448-23
Mechanistic insights into cell-free hemoglobin-induced injury during septic shock.
Wang Jeffrey,Applefeld Willard N,Sun Junfeng,Solomon Steve B,Feng Jing,Couse Zoe G,Risoleo Thomas F,Danner Robert L,Tejero Jesús,Lertora Juan,Alipour Elmira,Basu Swati,Sachdev Vandana,Kim-Shapiro Daniel B,Gladwin Mark T,Klein Harvey G,Natanson Charles
American journal of physiology. Heart and circulatory physiology
Cell-free hemoglobin (CFH) levels are elevated in septic shock and are higher in nonsurvivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. This study aimed to investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Fifty-one, 10-12 kg purpose-bred beagles were randomized to receive intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics and intensive care support for 96 h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and nonseptic animals, effects that were significantly greater in nonsurvivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis, and multiorgan failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in nonsurvivors. CFH-associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened pneumonia. Notably, cytokine levels were similar in survivors and nonsurvivors and were not predictive of outcome. In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention. Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.
10.1152/ajpheart.00092.2021
Lipocalin-2 is an essential component of the innate immune response to Acinetobacter baumannii infection.
PLoS pathogens
Acinetobacter baumannii is an opportunistic pathogen and an emerging global health threat. Within healthcare settings, major presentations of A. baumannii include bloodstream infections and ventilator-associated pneumonia. The increased prevalence of ventilated patients during the COVID-19 pandemic has led to a rise in secondary bacterial pneumonia caused by multidrug resistant (MDR) A. baumannii. Additionally, due to its MDR status and the lack of antimicrobial drugs in the development pipeline, the World Health Organization has designated carbapenem-resistant A. baumannii to be its priority critical pathogen for the development of novel therapeutics. To better inform the design of new treatment options, a comprehensive understanding of how the host contains A. baumannii infection is required. Here, we investigate the innate immune response to A. baumannii by assessing the impact of infection on host gene expression using NanoString technology. The transcriptional profile observed in the A. baumannii infected host is characteristic of Gram-negative bacteremia and reveals expression patterns consistent with the induction of nutritional immunity, a process by which the host exploits the availability of essential nutrient metals to curtail bacterial proliferation. The gene encoding for lipocalin-2 (Lcn2), a siderophore sequestering protein, was the most highly upregulated during A. baumannii bacteremia, of the targets assessed, and corresponds to robust LCN2 expression in tissues. Lcn2-/- mice exhibited distinct organ-specific gene expression changes including increased transcription of genes involved in metal sequestration, such as S100A8 and S100A9, suggesting a potential compensatory mechanism to perturbed metal homeostasis. In vitro, LCN2 inhibits the iron-dependent growth of A. baumannii and induces iron-regulated gene expression. To elucidate the role of LCN2 in infection, WT and Lcn2-/- mice were infected with A. baumannii using both bacteremia and pneumonia models. LCN2 was not required to control bacterial growth during bacteremia but was protective against mortality. In contrast, during pneumonia Lcn2-/- mice had increased bacterial burdens in all organs evaluated, suggesting that LCN2 plays an important role in inhibiting the survival and dissemination of A. baumannii. The control of A. baumannii infection by LCN2 is likely multifactorial, and our results suggest that impairment of iron acquisition by the pathogen is a contributing factor. Modulation of LCN2 expression or modifying the structure of LCN2 to expand upon its ability to sequester siderophores may thus represent feasible avenues for therapeutic development against this pathogen.
10.1371/journal.ppat.1010809
Baseline iron status and presence of anaemia determine the course of systemic Salmonella infection following oral iron supplementation in mice.
EBioMedicine
BACKGROUND:Iron deficiency anaemia (IDA) is a major health concern. However, preventive iron supplementation in regions with high burden of infectious diseases resulted in an increase of infection related morbidity and mortality. METHODS:We fed male C57BL/6N mice with either an iron deficient or an iron adequate diet. Next, they received oral iron supplementation or placebo followed by intraperitoneal infection with Salmonella Typhimurium (S.Tm). FINDINGS:We found that mice with IDA had a poorer clinical outcome than mice on an iron adequate diet. Interestingly, iron supplementation of IDA mice resulted in higher bacterial burden in organs and shortened survival. Increased transferrin saturation and non-transferrin bound iron in the circulation together with low expression of ferroportin facilitated the access of the pathogen to iron and promoted bacterial growth. Anaemia, independent of iron supplementation, was correlated with reduced neutrophil counts and cytotoxic T cells. With iron supplementation, anaemia additionally correlated with increased splenic levels of the cytokine IL-10, which is suggestive for a weakened immune control to S.Tm infection. INTERPRETATION:Supplementing iron to anaemic mice worsens the clinical course of bacterial infection. This can be traced back to increased iron delivery to bacteria along with an impaired anti-microbial immune response. Our findings may have important implications for iron supplementation strategies in areas with high endemic burden of infections, putting those individuals, who potentially profit most from iron supplementation for anaemia, at the highest risk for infections. FUNDING:Financial support by the Christian Doppler Laboratory for Iron Metabolism and Anemia Research.
10.1016/j.ebiom.2021.103568
What do we know about micronutrients in critically ill patients? A narrative review.
JPEN. Journal of parenteral and enteral nutrition
Micronutrient (MN) status alterations (both depletion and deficiency) are associated with several complications and worse outcomes in critically ill patients. On the other side of the spectrum, improving MN status has been shown to be a potential co-adjuvant therapy. This review aims to collect existing data to better guide research in the critical care setting. This narrative review was conducted by the European Society of Intensive Care Medicine Feeding, Rehabilitation, Endocrinology, and Metabolism MN group. The primary objective was to identify studies focusing on individual MNs in critically ill patients, selecting the MNs that appear to be most relevant and most frequently investigated in the last decade: A, B, B, B, B, folate, C, D, E, copper, iron, selenium, zinc, and carnitine. Given the limited number of interventional studies for most MNs, observational studies were included. For each selected MN, the review summarizes the main form and functions, special needs and risk factors, optimal treatment strategies, pharmacological dosing, and clinical implications all specific to critically ill patients. A rigorous rebalancing of research strategies and priorities is needed to improve clinical practice. An important finding is that high-dose monotherapy of MNs is not recommended. Basal daily needs must be provided, with higher doses in diseases with known higher needs, and identified deficiencies treated. Finally, the review provides a list of ongoing trials on MNs in critically ill patients and identifies a priority list of future research topics.
10.1002/jpen.2700
Serum trace element and heavy metal levels in patients with sepsis.
Akkaş İdris,Ince Nevin,Sungur Mehmet Ali
The aging male : the official journal of the International Society for the Study of the Aging Male
Sepsis is defined as a life-threatening organ dysfunction syndrome, which occurs when the body's immune response to infection is impaired. The aim of the present study was to investigate serum Iron, Copper, Zinco, Cobalt, Chromium, Selenium, Vanadium, Nickel, Cadmium, and Aliminium levels in patients with sepsis. This prospective and observational study was conducted at a tertiary care university hospital of Turkey from 2015 to 2016, and comprised patients with sepsis. Serum concentrations of 10 elements were analyzed using inductively coupled plasma mass spectrometry. Analyses were performed at the laboratory of Düzce University Scientific and Technological Research Application and Research Center. A total of 87 participants (52 men, 35 women; average age, 74.11 ± 14.26) were enrolled. When evaluated in terms of trace elements, a significant difference was noted between the sepsis and control groups in terms of the levels of the five elements. Chromium, Iron, Nickel, Copper, and Cadmium levels were significantly higher in the sepsis group. Our study indicated in particular, Iron, Copper, Chromium, Nickel, and Cadmium levels were elevated in patients with sepsis.
10.1080/13685538.2020.1740200
Hepcidin Exacerbates Iron Metabolism Imbalance in Septic Mice.
Infection and drug resistance
Purpose:Sepsis is a life-threatening condition associated with acute organ dysfunction. Iron is an essential trace element for multicellular organisms and almost all microorganisms, and its role in sepsis has been increasingly recognized. The aim of this study was to investigate the changes in iron metabolism in caecal ligation and puncture solution (CLP) -induced septic mice and the effects of hepcidin pretreatment on serum inflammatory marker levels and liver iron metabolism in CLP-induced septic mice. Methods:C57BL/6 mice were given normal saline, CLP (peritonitis model) or 100 μg of hepcidin via intraperitoneal injection. The experimental animals were divided into 4 groups: the control group, model group (CLP), hepcidin pretreatment Groups CLP+hepcidin-2h and CLP+hepcidin-24 h. Blood samples were collected at 6, 12 and 24 hours after CLP surgery, and the mice were euthanized and livers were obtained. Results:ELISA revealed that hepcidin pretreatment, especially 2 hours in advance (p<0.01), increased the serum hepcidin, TNF-a and IL-6 in CLP-induced septic mice; the serum iron content of CLP-related septic mice decreased (P<0.01), while the liver iron content increased (P<0.01); Hepcidin pretreatment reduced the serum iron (P<0.05) at 6 h and 12 h and liver iron concentrations (P<0.01) at 6 h, 12 h and 24 h in CLP-related septic mice. Western blotting revealed that the hepatic iron absorption-related proteins transferrin receptor-2 (TFR2), ZRT/IRT-like protein 14 (ZIP14) and divalent meta lion transporter-1 (DMT1) were elevated (P<0.01); The iron-exporting protein ferroportin (SLC40A1) was decreased (P<0.01) throughout CLP and CLP+hepcidin sepsis. Compared with CLP group, the protein expressions in the CLP+ hepcidin-2 h group were more obvious than that in the CLP+ hepcidin-24 h group. Conclusion:Hepcidin has proinflammatory effect. Hepcidin exacerbates iron metabolism imbalances in sepsis by influencing the expression of iron absorption-related proteins and iron export-related proteins.
10.2147/IDR.S484103
Ionic Modulation of Bacterial Virulence and Its Role in Surgical Infection.
Alverdy John C
Surgical infections
Bacterial virulence is a dynamic property of pathogens that is expressed in a context-dependent manner. For a bacterial pathogen, the expression of virulence is a tradeoff, as there is an energy cost that can disturb other functions. As a result, virulence is activated only when bacteria sense the need for it. Recent work from our laboratory has identified many of the local cues in the environmental context that activate bacterial virulence during surgical injury, resulting in bacterial invasion, tissue inflammation, and, in some cases, lethal sepsis. After surgical injury, cytokines, opioids, and end-products of ischemia can activate bacterial virulence circuits, such as the quorum-sensing signaling system, directly. However, when key ions are present, such as phosphate and iron, certain pathogenic bacteria become insensitive to these incoming host cues. In this review, we provide molecular insight into the process by which certain surgical infections may be prevented by ionic modulation of the local microenvironment.
10.1089/sur.2018.224
Co-Delivery of Renal Clearable Cerium Complex and Synergistic Antioxidant Iron Complex for Treating Sepsis.
ACS nano
The mononuclear phagocytic system clears the circulating inorganic nanomaterials from the bloodstream, which raises concerns about the chronic toxicity of the accumulated metal species. A better understanding of the behavior of each metal after systemic injection is thus required for clinical translations. This study investigates the significance of the metal-ligand interaction on the accumulation of cerium and demonstrates that only the form in which cerium is coordinated to a multidentate chelator with a strong binding affinity does not accumulate in major organs. Specifically, cerium complexed with diethylenetriamine pentaacetic acid (DTPA) forms renally excretable nanoparticles in vivo to circumvent the leaching of cerium ions, whereas weakly coordinated cerium-based nanomaterials produce insoluble precipitates upon encountering physiological phosphate anions. Ceria-based renally clearable nanoparticles (CRNs) derived from cerium-DTPA are utilized as the antioxidant pair with iron-DTPA, in which their combination leverages the Fenton reaction to synergistically scavenge hydrogen peroxide. This reduces the gene expression of pro-inflammatory factors in the macrophages activated with lipopolysaccharide as well as improves the survival rate of septic mice by alleviating the systemic inflammatory response and its downstream tissue injury in the liver, spleen, and kidneys. This study demonstrates that CRNs combined with iron-DTPA can be utilized as nonaccumulative nanomedicines for treating systemic inflammation, thereby overcoming the limitations of conventional ceria nanoparticle-based treatments.
10.1021/acsnano.4c05902
Longitudinal changes in iron homeostasis in human experimental and clinical malaria.
EBioMedicine
BACKGROUND:The interaction between iron status and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria. METHODS:We retrieved data and samples from 55 participants (19 female) enrolled in malaria VIS, and 171 patients (45 female) with malaria and 30 healthy controls (13 female) enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA. FINDINGS:In the VIS, participants' parasitaemia was correlated with baseline mean corpuscular volume (MCV), but not iron status (ferritin, hepcidin or sTfR). Ferritin, hepcidin and sTfR all increased during the VIS. Ferritin and hepcidin normalised by day 28, while sTfR remained elevated. In VIS participants, baseline ferritin was associated with post-treatment increases in liver transaminase levels. In Malaysian patients with malaria, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. By day 28, hepcidin had normalised; however, ferritin and sTfR both remained elevated. INTERPRETATION:Our findings demonstrate that parasitaemia is associated with an individual's MCV rather than iron status. The persistent elevation in sTfR 4 weeks post-infection in both malaria VIS and clinical malaria may reflect a causal link between malaria and iron deficiency. FUNDING:National Health and Medical Research Council (Program Grant 1037304, Project Grants 1045156 and 1156809; Investigator Grants 2016792 to BEB, 2016396 to JCM, 2017436 to MJG); US National Institute of Health (R01-AI116472-03); Malaysian Ministry of Health (BP00500420).
10.1016/j.ebiom.2024.105189
Role of divalent metals in infectious disease susceptibility and outcome.
Weiss G,Carver P L
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
BACKGROUND:Divalent metals play important roles in maintaining metabolism and cellular growth of both eukaryotic hosts and invading microbes. Both metal deficiency and overload can result in abnormal cellular function or damage. Given its central role in host-pathogen interactions, subtle alterations of divalent metal homeostasis can occur in the course of infectious diseases which aim, from the host perspective, either to reduce the availability of respective metals to microbes or to use toxic metal accumulation to eliminate pathogens. AIMS:To provide the reader with background information and clinical data on divalent metal homeostasis in host-pathogen interactions, how this affects the course of infectious disease and whether correction of metal disturbances has shown benefit in infections. SOURCES:An in-depth analysis of PubMed articles related to the topic of this review published in English between 1970 and 2016 was performed. CONTENT:From the microbial perspective, divalent metals are essential for growth and pathogenicity and to mount effective protection against antimicrobial host responses, including toxic radical formation. Microbes have evolved multiple strategies to control their access to divalent metals. From the clinical perspective, alterations of divalent metal levels may result in increased or decreased susceptibility to infection and often occur in response to infections. However, keeping in mind the strategies underlying such alterations, for which the term 'nutritional immunity' was coined, the uncritical correction of such divalent metal imbalances may cause harm to patients. This review addresses the role of the divalent metals iron, selenium, zinc, manganese and copper in infectious diseases from a mechanistic and clinical perspective. IMPLICATIONS:We point out areas of research needed to expand our limited knowledge, hoping to improve the clinical management of patients with infections and to identify promising new targets for treatment by modulation of host or microbe divalent metal metabolism.
10.1016/j.cmi.2017.01.018
Dysregulated myelopoiesis and hematopoietic function following acute physiologic insult.
Loftus Tyler J,Mohr Alicia M,Moldawer Lyle L
Current opinion in hematology
PURPOSE OF REVIEW:The purpose of this review is to describe recent findings in the context of previous work regarding dysregulated myelopoiesis and hematopoietic function following an acute physiologic insult, focusing on the expansion and persistence of myeloid-deriver suppressor cells, the deterioration of lymphocyte number and function, and the inadequacy of stress erythropoiesis. RECENT FINDINGS:Persistent myeloid-derived suppressor cell (MDSC) expansion among critically ill septic patients is associated with T-cell suppression, vulnerability to nosocomial infection, chronic critical illness, and poor long-term functional status. Multiple approaches targeting MDSC expansion and suppressor cell activity may serve as a primary or adjunctive therapeutic intervention. Traumatic injury and the neuroendocrine stress response suppress bone marrow erythropoietin receptor expression in a process that may be reversed by nonselective beta-adrenergic receptor blockade. Hepcidin-mediated iron-restricted anemia of critical illness requires further investigation of novel approaches involving erythropoiesis-stimulating agents, iron administration, and hepcidin modulation. SUMMARY:Emergency myelopoiesis is a dynamic process with unique phenotypes for different physiologic insults and host factors. Following an acute physiologic insult, critically ill patients are subject to persistent MDSC expansion, deterioration of lymphocyte number and function, and inadequate stress erythropoiesis. Better strategies are required to identify patients who are most likely to benefit from targeted therapies.
10.1097/MOH.0000000000000395
Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release.
Scientific reports
Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines, chemokines and neutrophil extracellular traps (NETs). In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by a range of chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits neutrophil motility. In murine infection models, artemisinin potently suppressed neutrophil invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and NETs. This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death.
10.1038/s41598-022-15214-6
[Research progress on the mechanism of ferroptosis in septic cardiomyopathy].
Zhonghua wei zhong bing ji jiu yi xue
Sepsis is a serious complication of infection, and its further development may lead to multi-organ dysfunction syndrome. Sepsis cardiomyopathy is a common complication of sepsis and has been directly linked to high mortality. Although the pathogenesis of septic cardiomyopathy is not fully understood, in-depth study of the pathogenesis of septic cardiomyopathy and the identification of its potential therapeutic targets may reduce mortality in patients with sepsis. Ferroptosis is an iron-dependent mode of cell death that has been shown to be involved in the pathophysiological mechanisms of many diseases. Some related studies have reported that ferroptosis may be a potential mechanism of septic cardiomyopathy. This review provides new insights into the mechanisms of mitochondrial dysfunction, lipid peroxidation, xc-system, glutathione peroxidase 4 (GPX4), iron metabolism and the role of ferroptosiswith septic cardiomyopathy for further research and treatment of septic cardiomyopathy.
10.3760/cma.j.cn121430-20220823-00776
NDUFS3 alleviates oxidative stress and ferroptosis in sepsis induced acute kidney injury through AMPK pathway.
International immunopharmacology
In recent years, ferroptosis has been found to play an important role in various acute kidney injury (AKI). However, relatively little research has been conducted on sepsis-induced acute kidney injury (SI-AKI). As an important trigger of ferroptosis, how mitochondrial damage plays a regulatory role in SI-AKI is still unclear. To explore the potential relationship between mitochondria and ferroptosis, we established a SI-AKI rat model by intraperitoneal injection of lipopolysaccharide (LPS). Transcriptome sequencing was used to detect changes in gene transcription levels in the control group, LPS 3 h group, LPS 6 h group and LPS 12 h group. The severity of kidney injury was determined based on serum creatinine (CRE), blood urea nitrogen (BUN), tissue HE staining, TUNEL staining and inflammatory factor levels. Cytoscape software was utilized to screen several mitochondria-related HUB genes, and NADH dehydrogenase [ubiquinone] ferrithionein 3 (NDUFS3) was selected for subsequent validation due to its novelty and feasibility. qRT-PCR, Western blot was employed to evaluate the expression of NDUFS3 in kidney tissues. GO enrichment analysis revealed that up-regulated genes in the LPS 12 h group were enriched in several cell death terms while down-regulated genes were enriched in lipid metabolic process and oxidation-reduction progress terms. Furthermore, Western blot, IHC, MDA, GSH and iron content levels were used to assess ferroptosis in the kidney tissue of the SI-AKI rats, dihydroethidium (DHE) assay and ATP kit were used to assess mitochondrial ROS levels and mitochondrial function. To further validate the function of NDUFS3, we constructed overexpression rats using hydrodynamic method by tail vein injection of pc DNA3.1-NDUFS3 overexpression plasmid. we utilized LPS to stimulate HK-2 cells and establish an in vitro model. We then overexpressed NDUFS3 using pcDNA 3.1. The overexpression of NDUFS3 was found to inhibit LPS-induced ferroptosis and mitochondrial damage in HK-2 cells, as evidenced by Western blot, MDA, GSH, divalent iron, ROS levels, Mitosox red, ATP content and transmission electron microscopy. Finally, the use of Compound C to inhibit AMPK in HK-2 cells demonstrated that NDUFS3 plays a protective role through the AMPK pathway. Therefore, our study supports the emerging role of NDUFS3 in SI-AKI, providing new potential mitochondria-related targets for the treatment of SI-AKI.
10.1016/j.intimp.2024.113393
Notoginsenoside R1 treatment facilitated Nrf2 nuclear translocation to suppress ferroptosis via Keap1/Nrf2 signaling pathway to alleviated high-altitude myocardial injury.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
High-altitude myocardial injury (HAMI) represents a critical form of altitude illness for which effective drug therapies are generally lacking. Notoginsenoside R1, a prominent constituent derived from Panax notoginseng, has demonstrated various cardioprotective properties in models of myocardial ischemia/reperfusion injury, sepsis-induced cardiomyopathy, cardiac fibrosis, and myocardial injury. The potential utility of notoginsenoside R1 in the management of HAMI warrants prompt investigation. Following the successful construction of a HAMI model, a series of experimental analyses were conducted to assess the effects of notoginsenoside R1 at dosages of 50 mg/Kg and 100 mg/Kg. The results indicated that notoginsenoside R1 exhibited protective effects against hypoxic injury by reducing levels of CK, CK-MB, LDH, and BNP, leading to improved cardiac function and decreased incidence of arrhythmias. Furthermore, notoginsenoside R1 was found to enhance Nrf2 nuclear translocation, subsequently regulating the SLC7A11/GPX4/HO-1 pathway and iron metabolism to mitigate ferroptosis, thereby mitigating cardiac inflammation and oxidative stress induced by high-altitude conditions. In addition, the application of ML385 has confirmed the involvement of Nrf2 nuclear translocation in the therapeutic approach to HAMI. Collectively, the advantageous impacts of notoginsenoside R1 on HAMI have been linked to the suppression of ferroptosis via Nrf2 nuclear translocation signaling.
10.1016/j.biopha.2024.116793
The Mechanisms of Action of Hyperbaric Oxygen in Restoring Host Homeostasis during Sepsis.
Biomolecules
The perception of sepsis has shifted over time; however, it remains a leading cause of death worldwide. Sepsis is now recognized as an imbalance in host cellular functions triggered by the invading pathogens, both related to immune cells, endothelial function, glucose and oxygen metabolism, tissue repair and restoration. Many of these key mechanisms in sepsis are also targets of hyperbaric oxygen (HBO) treatment. HBO treatment has been shown to improve survival in clinical studies on patients with necrotizing soft tissue infections as well as experimental sepsis models. High tissue oxygen tension during HBO treatment may affect oxidative phosphorylation in mitochondria. Oxygen is converted to energy, and, as a natural byproduct, reactive oxygen species are produced. Reactive oxygen species can act as mediators, and both these and the HBO-mediated increase in oxygen supply have the potential to influence the cellular processes involved in sepsis. The pathophysiology of sepsis can be explained comprehensively through resistance and tolerance to infection. We argue that HBO treatment may protect the host from collateral tissue damage during resistance by reducing neutrophil extracellular traps, inhibiting neutrophil adhesion to vascular endothelium, reducing proinflammatory cytokines, and halting the Warburg effect, while also assisting the host in tolerance to infection by reducing iron-mediated injury and upregulating anti-inflammatory measures. Finally, we show how inflammation and oxygen-sensing pathways are connected on the cellular level in a self-reinforcing and detrimental manner in inflammatory conditions, and with support from a substantial body of studies from the literature, we conclude by demonstrating that HBO treatment can intervene to maintain homeostasis.
10.3390/biom13081228
Nrf2 mitigates sepsis-associated encephalopathy-induced hippocampus ferroptosis via modulating mitochondrial dynamic homeostasis.
International immunopharmacology
Sepsis-associated encephalopathy (SAE) is a serious neurological complication accompanied with acute and long-term cognitive dysfunction. Ferroptosis is a newly discovered type of cell death that is produced by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis is involved in SAE. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a mitochondria related gene involved in ferroptosis. However, the role of Nrf2 in SAE and the mechanisms remains elusive. In this study, we found that Nrf2 knockout aggravated cognitive and emotional dysfunction and promoted caecal ligation and puncture (CLP)-induced brain injury and hippocampus ferroptosis as indicated by the increase of ROS, Fe and the levels of proinflammatory cytokines. Meanwhile, the levels of glutathione peroxidase 4 (GPX4), SLC7A11 and glutathionewere downregulatedin Nrf2 knockout group. In vitro experiments showed that mitochondrial ROS, Fe and the expression of Fis1 and Drp1 decreased, and the level of Mfn1 and Opa-1 increased after Nrf2 overexpression. The silence of Nrf2 increased the expression of ROS, MDA and Fe, while decreased glutathione, mitochondrial membrane potential (MMP) and cell viability in vitro, indicating Nrf2 improved LPS-induced mitochondrial dysfunction and mitigated hippocampal cells ferroptosis. These results suggest that Nrf2 could inhibit ferroptosis and neuroinflammation in hippocampus and reduce cognitive dysfunction in SAE mice, making it a potential therapeutic target in the treatment of SAE. The protective effects of Nrf2 on the brain may be mediated by maintaining mitochondrial dynamic homeostasis.
10.1016/j.intimp.2024.113331
Dapagliflozin attenuates LPS-induced myocardial injury by reducing ferroptosis.
Journal of bioenergetics and biomembranes
Septic cardiomyopathy is a severe cardiovascular disease with a poor prognosis. Previous studies have reported the involvement of ferroptosis in the pathogenesis of septic cardiomyopathy. SGLT2 inhibitors such as dapagliflozin have been demonstrated to improve ischemia-reperfusion injury by alleviating ferroptosis in cardiomyocyte. However, the role of dapagliflozin in sepsis remains unclear. Therefore, our study aims to investigate the therapeutic effects of dapagliflozin on LPS-induced septic cardiomyopathy. Our results indicate that dapagliflozin improved cardiac function in septic cardiomyopathy experimental mice. Mechanistically, dapagliflozin works by inhibiting the translation of key proteins involved in ferroptosis, such as GPX4, FTH1, and SLC7A11. It also reduces the transcription of lipid peroxidation-related mRNAs, including PTGS2 and ACSL4, as well as iron metabolism genes TFRC and HMOX1.
10.1007/s10863-024-10020-3
Effect of Sepsis on Iron Parameters in a Population with High Prevalence of Malnutrition and Iron Deficiency: A Cross-Sectional Case-Control Pilot Study.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion
There is lack of data on iron metabolism in critically ill sepsis children from population with high prevalence of iron deficiency (ID). The study was designed to study impact of sepsis on iron parameters in children with ID. Sepsis patients (age 6-59 months) and their apparently healthy sibling/cousin as controls were enrolled in this case-control pilot study. Serum iron, TIBC, transferrin saturation, ferritin and sTfR were measured in the two groups. sTfR-Ferritin index was calculated. Patients ( = 134) were significantly underweight compared to controls ( = 54) (WAZ score < - 2; 58% vs. 28%; < 0.001). Serum iron and sTfR (mg/L) were lower [71.5 (51.0, 115.0) vs. 87.0 (64.5, 130.5), = 0.068; 3.1 (2.1, 4.5) vs. 3.5 (2.8, 4.8), = 0.026 respectively] while serum ferritin was higher [229 (94, 484.5) vs. 22 (9.2, 51); < 0.001] in patients compared to controls. sTfR-Ferritin index was lower in patients [1.3 (0.8, 2.3) vs. 2.5 (1.8, 4.5); < 0.001]. ROC AUC (patients vs. controls) were 0.89 (95% CI 0.83-0.95) and 0.76 (95% CI 0.68-0.85) for ferritin and sTfR-ferritin index respectively. Survivors and non-survivors were similar in terms of iron parameters. Sepsis-induced alterations in iron parameters among ID children are complex. Qualitatively it is similar (with quantitative differences) to non-ID adult population. Lack of correlation of iron parameters with mortality may be due to ID-associated immune dysfunction.
10.1007/s12288-020-01393-7
Propofol and Dexmedetomidine Ameliorate Endotoxemia-Associated Encephalopathy via Inhibiting Ferroptosis.
Drug design, development and therapy
Background:Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation. Methods:A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1 and GFAP cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of and ; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated. Conclusion:The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.
10.2147/DDDT.S458013
Iron, hemochromatosis genotypes, and risk of infections: a cohort study of 142 188 general population individuals.
Blood
ABSTRACT:It is unclear whether risk of infection is increased in individuals with hereditary hemochromatosis and in individuals with low or high plasma iron, transferrin saturation, or ferritin. Therefore, we tested whether high and low iron, transferrin saturation, and ferritin are associated with risk of infections observationally and genetically through HFE genotypes. We studied 142 188 Danish general population individuals. Iron, transferrin saturation, and ferritin were measured in 136 656, 136 599, and 38 020 individuals, respectively. HFE was genotyped for C282Y and H63D in 132 542 individuals. Median follow-up after study enrollment was 8 years (range, 0-38) for hospital and emergency room admissions with infections (n = 20 394) using the National Patient Register, covering all Danish hospitals. Hazard ratios for any infection were 1.20 (95% confidence interval [CI], 1.12-1.28) and 1.14 (95% CI, 1.07-1.22) in individuals with plasma iron ≤5th or ≥95th percentile compared with individuals with iron from 26th to 74th percentiles. Findings for transferrin saturation were similar, whereas infection risk was not increased in individuals with ferritin ≤5th or ≥95th percentile. Hazard ratios in C282Y homozygotes vs noncarriers were 1.40 (95% CI, 1.16-1.68) for any infection, 1.69 (95% CI, 1.05-2.73) for sepsis, and 2.34 (95% CI, 1.41-3.90) for death from infectious disease. Risk of infection was increased in C282Y homozygotes with normal plasma iron, transferrin saturation, or ferritin, and in C282Y homozygotes without liver disease, diabetes, and/or heart failure. In summary, low and high plasma iron and transferrin saturation were independently associated with increased infection risk. C282Y homozygotes had increased risk of any infection, sepsis, and death from infections. Even C282Y homozygotes with normal iron, transferrin saturation, or ferritin, not currently recommended for genotyping, had increased infection risk.
10.1182/blood.2023022235
Role of iron in the treatment of sepsis.
Biointerphases
Iron is an important microelement in human and microbial life activities. During the pathophysiological process of sepsis, iron metabolism changes and the body undergoes a series of changes to fight microbial infection. Meanwhile, alterations in iron metabolism during sepsis lead to the development of some diseases, such as transfusion-induced siderosis and anemia. In recent years, several studies have demonstrated the use of iron-chelating agents to fight microbial infections, and new antimicrobial agents have been developed using "Trojan horse" and siderophores immunity. In addition, the use of iron-based nanomaterials as drug delivery systems for gene delivery may be applied to the treatment of sepsis in the future. In this review, we describe the pathophysiological changes in the development and course of sepsis, focusing on the potential of iron in the treatment of sepsis.
10.1116/6.0003879
Lysosomal iron recycling in mouse macrophages is dependent upon both LcytB and Steap3 reductases.
Blood advances
Iron that is stored in macrophages as ferritin can be made bioavailable by degrading ferritin in the lysosome and releasing iron back into the cytosol. Iron stored in ferritin is found as Fe3+ and must be reduced to Fe2+ before it can be exported from the lysosome. Here we report that the lysosomal reductase Cyb561a3 (LcytB) and the endosomal reductase six-transmembrane epithelial antigen of prostate 3 (Steap3) act as lysosomal ferrireductases in the mouse macrophage cell line RAW264.7 converting Fe3+ to Fe2+ for iron recycling. We determined that when lysosomes were loaded with horse cationic ferritin, reductions or loss of LcytB or Steap3 using CRISPR/Cas9-mediated knockout technology resulted in decreased lysosomal iron export. Loss of both reductases was additive in decreasing lysosomal iron export. Decreased reductase activity resulted in increased transcripts for iron acquisition proteins DMT1 and transferrin receptor 1 (Tfrc1) suggesting that cells were iron limited. We show that transcript expression of LcytB and Steap3 is decreased in macrophages exposed to Escherichia coli pathogen UTI89, which supports a role for these reductases in regulating iron availability for pathogens. We further show that loss of LcytB and Steap3 in macrophages infected with UTI89 led to increased proliferation of intracellular UTI89 suggesting that the endolysosomal system is retaining Fe3+ that can be used for proliferation of intravesicular pathogens. Together, our findings reveal an important role for both LcytB and Steap3 in macrophage iron recycling and suggest that limiting iron recycling by decreasing expression of endolysosomal reductases is an innate immune response to protect against pathogen proliferation and sepsis.
10.1182/bloodadvances.2021005609
The connection between autophagy and ferroptosis in AKI: recent advances regarding selective autophagy.
Renal failure
Acute kidney injury (AKI) is a significant issue in public health, displaying a high occurrence rate and mortality rate. Ferroptosis, a form of programmed cell death (PCD), is characterized by iron accumulation and intensified lipid peroxidation. Recent studies have demonstrated the pivotal significance of ferroptosis in AKI caused by diverse stimuli, including ischemia-reperfusion injury (IRI), sepsis and toxins. Autophagy, a multistep process that targets damaged organelles and macromolecules for degradation and recycling, also plays an essential role in AKI. Previous research has demonstrated that autophagy deletion in proximal tubules could aggravate tubular injury and renal function loss, indicating the protective function of autophagy in AKI. Consequently, finding ways to stimulate autophagy has become a crucial therapeutic strategy. The recent discovery of the role of selective autophagy in influencing ferroptosis has identified new therapeutic targets for AKI and has highlighted the importance of understanding the cross-talk between autophagy and ferroptosis. This study aims to provide an overview of the signaling pathways involved in ferroptosis and autophagy, focusing on the mechanisms and functions of selective autophagy and autophagy-dependent ferroptosis. We hope to establish a foundation for future investigations into the interaction between autophagy and ferroptosis in AKI as well as other diseases.
10.1080/0886022X.2024.2379601
The role of neutrophil gelatinase-associated lipocalin and iron homeostasis in object recognition impairment in aged sepsis-survivor rats.
Scientific reports
Older adult patients with sepsis frequently experience cognitive impairment. The roles of brain neutrophil gelatinase-associated lipocalin (NGAL) and iron in older sepsis patients remain unknown. We investigated the effects of lipopolysaccharide-induced sepsis on novel object recognition test, NGAL levels, an inflammatory mediator tumor necrosis factor-α (TNFα) levels, and iron ion levels in the hippocampus and cortex of young and aged rats. The effect of an iron chelator deferoxamine pretreatment on aged sepsis rats was also examined. Young sepsis-survivor rats did not show impaired novel object recognition, TNFα responses, or a Fe/Fe imbalance. They showed hippocampal and cortical NGAL level elevations. Aged sepsis-survivor rats displayed a decreased object discrimination index, elevation of NGAL levels and Fe/Fe ratio, and no TNFα responses. Pretreatment with deferoxamine prevented the reduction in the object recognition of aged sepsis-survivor rats. The elevation in hippocampal and cortical NGAL levels caused by lipopolysaccharide was not influenced by deferoxamine pretreatment. The lipopolysaccharide-induced Fe/Fe ratio elevation was blocked by deferoxamine pretreatment. In conclusion, our findings suggest that iron homeostasis in the cortex and hippocampus contributes to the maintenance of object recognition ability in older sepsis survivors.
10.1038/s41598-021-03981-7
Ferroptosis contributes to immunosuppression.
Frontiers of medicine
As a novel form of cell death, ferroptosis is mainly regulated by the accumulation of soluble iron ions in the cytoplasm and the production of lipid peroxides and is closely associated with several diseases, including acute kidney injury, ischemic reperfusion injury, neurodegenerative diseases, and cancer. The term "immunosuppression" refers to various factors that can directly harm immune cells' structure and function and affect the synthesis, release, and biological activity of immune molecules, leading to the insufficient response of the immune system to antigen production, failure to successfully resist the invasion of foreign pathogens, and even organ damage and metabolic disorders. An immunosuppressive phase commonly occurs in the progression of many ferroptosis-related diseases, and ferroptosis can directly inhibit immune cell function. However, the relationship between ferroptosis and immunosuppression has not yet been published due to their complicated interactions in various diseases. Therefore, this review deeply discusses the contribution of ferroptosis to immunosuppression in specific cases. In addition to offering new therapeutic targets for ferroptosis-related diseases, the findings will help clarify the issues on how ferroptosis contributes to immunosuppression.
10.1007/s11684-024-1080-8
The clinical relevance of heme detoxification by the macrophage heme oxygenase system.
Frontiers in immunology
Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express HMOX1 and 2 and are critical sites of heme degradation in healthy and diseased states. Here we review the functions of the macrophage heme oxygenase system and its clinical relevance in discrete groups of pathologies where heme has been demonstrated to play a driving role. HMOX1 function in macrophages is essential for limiting oxidative tissue damage in both acute and chronic hemolytic disorders. By degrading pro-inflammatory heme and releasing anti-inflammatory molecules such as carbon monoxide, HMOX1 fine-tunes the acute inflammatory response with consequences for disorders of hyperinflammation such as sepsis. We then discuss divergent beneficial and pathological roles for HMOX1 in disorders such as atherosclerosis and metabolic syndrome, where activation of the HMOX system sits at the crossroads of chronic low-grade inflammation and oxidative stress. Finally, we highlight the emerging role for HMOX1 in regulating macrophage cell death via the iron- and oxidation-dependent form of cell death, ferroptosis. In summary, the importance of heme clearance by macrophages is an active area of investigation with relevance for therapeutic intervention in a diverse array of human diseases.
10.3389/fimmu.2024.1379967
CircEXOC5 Aggravates Sepsis-Induced Acute Lung Injury by Promoting Ferroptosis Through the IGF2BP2/ATF3 Axis.
The Journal of infectious diseases
BACKGROUND:Patients with sepsis resulting in acute lung injury (ALI) usually have increased mortality. Ferroptosis is a vital regulator in sepsis-induced ALI. Exploring the association of ferroptosis and sepsis-induced ALI is crucial for the management of sepsis-induced ALI. METHODS:Whole blood was collected from sepsis patients. Mice were treated with cecal ligation and puncture (CLP) to model sepsis. Primary murine pulmonary microvascular endothelial cells were treated with lipopolysaccharide as a cell model. Ferroptosis was evaluated by analyzing levels of iron, malonaldehyde, glutathione, nonheme iron, ferroportin, ferritin, and GPX4. Hematoxylin and eosin and Masson's trichrome staining were applied to examine lung injury and collagen deposition. Cell apoptosis was analyzed by caspase-3 activity and TUNEL assays. Gene regulatory relationship was verified using RNA pull-down and immunoprecipitation assays. RESULTS:CircEXOC5 was highly expressed in sepsis patients and CLP-treated mice, in which knockdown alleviated CLP-induced pulmonary inflammation and injury, and ferroptosis. CircEXOC5 recruited IGF2BP2 to degrade ATF3 mRNA. The demethylase ALKBH5 was responsible for circEXOC5 upregulation through demethylation. CircEXOC5 silencing significantly improved sepsis-induced ALI and survival rate of mice by downregulating ATF3. CONCLUSIONS:ALKBH5-mediated upregulation of circEXOC5 exacerbates sepsis-induced ALI by facilitating ferroptosis through IGF2BP2 recruitment to degrade ATF3 mRNA.
10.1093/infdis/jiad337
Dynamics of iron metabolism in patients with bloodstream infections: a time-course clinical study.
Scientific reports
The close relationship between infectious diseases and iron metabolism is well known, but a more detailed understanding based on current knowledge may provide new insights into the diagnosis and treatment of infectious diseases, considering the growing threat of antibiotic-resistant bacteria. This study investigated adult patients with bloodstream infections, temporal changes, and relationships between blood levels of iron and related markers, including hepcidin and lipocalin-2 (LCN2). We included 144 samples from 48 patients (mean age 72 years, 50% male), with 30 diagnosed with sepsis. During the acute phase of infection, blood levels of hepcidin and LCN2 increased rapidly, whereas iron levels decreased, with values in 95.8% of cases below the normal range (40-188 μg/dL). Later, hepcidin and LCN2 decreased significantly during the recovery phase, and the decreased iron concentrations were restored. In the case of persistent inflammation, iron remained decreased. Acute LCN2 levels were significantly higher in patients with sepsis (p < 0.01). Hypoferremia induced by increased hepcidin would reduce iron in the environment of extracellular pathogens, and the increased LCN2 would inhibit siderophores, resulting in the prevention of the pathogen's iron acquisition in each manner during the acute phase of bloodstream infection.
10.1038/s41598-023-46383-7
YIQIFUMAI INJECTION AMELIORATED SEPSIS-INDUCED CARDIOMYOPATHY BY INHIBITION OF FERROPTOSIS VIA XCT/GPX4 AXIS.
Shock (Augusta, Ga.)
ABSTRACT:Sepsis-induced cardiomyopathy ( SIC ) is a distinct form of myocardial injury that disrupts tissue perfusion and stands as the significant cause of mortality among sepsis patients. Currently, effective preventive or treatment strategies for SIC are lacking. YiQiFuMai injection (YQFM), composed of Panax ginseng C.A. Mey., Ophiopogon japonicus (Thunb.) Ker Gawl., and Schisandra chinensis (Turcz.) Baill., is widely used in China to treat cardiovascular diseases, such as coronary heart disease, heart failure, and SIC . Research has shown that YQFM can improve cardiac function and alleviate heart failure through multiple pathways. Nevertheless, the mechanisms through which YQFM exerts its effects on SIC remain to be fully elucidated. In this study, we firstly investigated the therapeutic effects of YQFM on a SIC rat model and explored its effects on myocardial ferroptosis in vivo. Then, LPS-induced myocardial cell death model was used to evaluate the effects of YQFM on ferroptosis and xCT/GPX4 axis in vitro . Furthermore, using GPX4 inhibitors, we aimed to verify whether YQFM improved cardiomyocyte ferroptosis through the xCT/GPX4 axis. The results showed that YQFM was effective in alleviating myocardial injury in septic model rats. Besides, the concentrations of iron and the levels of lipid peroxidation-related factors (ROS, MDA, and 4-HNE) were significantly decreased and the expression of xCT/GPX4 axis was upregulated in SIC rats after YQFM treatment. In vitro studies also showed that YQFM alleviated iron overload and lipid peroxidation and activated xCT/GPX4 axis in LPS-induced myocardial cell death model. Moreover, GPX4 inhibitor could abolish the effects above. In summary, the study highlights the regulatory effect of YQFM in mitigating myocardial injury. It probably achieves this ameliorative effect by enhancing xCT/GPX4 axis and further reducing ferroptosis.
10.1097/SHK.0000000000002257
Inhibition of ferroptosis protects sepsis-associated encephalopathy.
Cytokine
Sepsis-associated encephalopathy (SAE) is a serious and common complication of sepsis. To study the ferroptosis in the pathogenesis of SAE and demonstrate the protection effect of ferroptosis resistance, cognitive function, neurological deficits, blood-brain barrier integrity and neuroinflammation were detected. SAE model was established by cecal ligation and puncture (CLP) in mice and an in vitro model was created by introducing LPS to HT22 cells. Ferroptosis inducer Fe-citrate (Fe) and ferroptosis inhibitor ferrostatin-1 (Fer-1) was post-treated in the models, respectively. SAE caused ferroptosis, as evidenced by an increase in reactive oxygen species (ROS), iron content and malondialdehyde (MDA) and a decrease in glutathione (GSH) level, as well as changes in the expression of ferroptosis-related proteins as acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), and cystine-glutamate antiporter (SLC7A11), and harmed mitochondrial function. In contrast, inhibiting ferroptosis with Fer-1 attenuated ferroptosis. Meanwhile, Fer-1 attenuated neurologic severity score, learning and memory impairment, Fluoro-Jade C (FJC) staining, and decreased Evans Blue (EB) extravasation, microglia activation and TNF-α and IL-1β production following SAE. The benefit of Fer-1 was diminished by ferroptosis inducer Fe. In addition, Fer-1 up-regulated the nuclear factor erythroid-2-related factor 2 (Nrf2)/ heme oxygenase-1(HO-1) signaling axis both in vivo and in vitro. In conclusion, our study revealed that Fer-1 might inhibit feroptosis in neurons by triggering the Nrf2/OH-1 pathway, thereby providing a therapeutic solution for SAE.
10.1016/j.cyto.2022.156078
STAT3-Mediated Ferroptosis is Involved in Sepsis-Associated Acute Respiratory Distress Syndrome.
Inflammation
Sepsis-induced acute respiratory distress syndrome (ARDS) poses a grave danger to life, resulting from sepsis-induced multi-organ failure. Although ferroptosis, a form of iron-dependent lipid peroxidative cell death, has been associated with sepsis-induced ARDS, the specific mechanisms are not fully understood. In this study, we utilized WGCNA, PPI, friends analysis, and six machine learning techniques (Lasso, SVM, RFB, XGBoost, AdaBoost, and LightGBM) to pinpoint STAT3 as a potential diagnostic marker. A significant increase in monocyte and neutrophil levels was observed in patients with sepsis-induced ARDS, as revealed by immune infiltration analyses, when compared to controls. Moreover, there was a positive correlation between STAT3 expression and the level of infiltration. Single-cell analysis uncovered a notable disparity in B-cell expression between sepsis and sepsis-induced ARDS. Furthermore, in vitro experiments using LPS-treated human bronchial epithelial cells (BEAS-2B) and THP1 cells demonstrated a significant increase in STAT3 phosphorylation expression. Additionally, the inhibition of STAT3 phosphorylation by Stattic effectively prevented LPS-induced ferroptosis in both BEAS-2B and THP1 cells. This indicates that the activation of STAT3 phosphorylation promotes ferroptosis in human bronchial epithelial cells in response to LPS. In summary, this research has discovered and confirmed STAT3 as a potential biomarker for the diagnosis and treatment of sepsis-induced ARDS.
10.1007/s10753-024-01970-2
Deciphering the iron enigma: Navigating the complexities of iron metabolism in critical illness.
World journal of clinical cases
Iron is a double-edged sword! Despite being essential for numerous physiological processes of the body, a dysregulated iron metabolism can result in tissue damage, exaggerated inflammatory response, and increased susceptibility to infection with certain pathogens that thrive in iron-rich environment. During sepsis, there is an alteration of iron metabolism, leading to increased transport and uptake into cells. This increase in labile iron may cause oxidative damage and cellular injury (ferroptosis) which progresses as the disease worsens. Critically ill patients are often complicated with systemic inflammation which may contribute to multiple organ dysfunction syndrome or sepsis, a common cause of mortality in intensive care unit. Originally, ferritin was known to play an important role in the hematopoietic system for its iron storage capacity. Recently, its role has emerged as a predictor of poor prognosis in chronic inflammation and critical illnesses. Apart from predicting the disease outcome, serum ferritin can potentially reflect disease activity as well.
10.12998/wjcc.v12.i27.6027
The Emerging Role of Ferroptosis in Sepsis, Opportunity or Challenge?
Infection and drug resistance
Sepsis is a syndrome in multi-organ dysfunction triggered by a deleterious immunological reaction of the body to a condition caused by infection, surgery, or trauma. Currently, sepsis is thought to be primarily associated with abnormal immune responses resulting in organ microcirculatory disturbances, cellular mitochondrial dysfunction, and induced cell death, although the exact pathogenesis of sepsis is still inconclusive. In recent years, the role of abnormal metabolism of trace nutrients in the pathogenesis of sepsis has been investigated. Ferroptosis is a type of cell death that relies on iron and is characterized by unique morphological, biochemical, and genetic features. Unlike other forms of cell death, such as autophagy, apoptosis, necrosis, and pyroptosis, ferroptosis is primarily driven by lipid peroxidation. Ferroptosis cells may be immunogenic, amplify inflammatory responses, cause more cell death, and ultimately induce multi-organ failure. An increasing number of studies have indicated the significance of ferroptosis in sepsis and its role in reducing inflammation. The effectiveness of sepsis treatment has been demonstrated by the use of drugs that specifically target molecules associated with the ferroptosis pathway, including ferroptosis inhibitors. Nevertheless, there is a scarcity of studies investigating the multi-organ dysfunction caused by ferroptosis in sepsis. This article presents a summary and evaluation of recent progress in the role of ferroptosis through molecularly regulated mechanisms and its potential mechanisms of action in the multi-organ dysfunction associated with sepsis. It also discusses the current challenges and prospects in understanding the connection between sepsis and ferroptosis, and proposes innovative ideas and strategies for the treatment of sepsis.
10.2147/IDR.S419993
Ferritin heavy chain supports stability and function of the regulatory T cell lineage.
The EMBO journal
Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.
10.1038/s44318-024-00064-x
Ribonuclease inhibitor 1 emerges as a potential biomarker and modulates inflammation and iron homeostasis in sepsis.
Scientific reports
Sepsis, marked by organ dysfunction, necessitates reliable biomarkers. Ribonuclease inhibitor 1 (RNH1), a ribonuclease (RNase) inhibitor, emerged as a potential biomarker for acute kidney injury and mortality in thoracoabdominal aortic aneurysm patients. Our study investigates RNH1 dynamics in sepsis, its links to mortality and organ dysfunction, and the interplay with RNase 1 and RNase 5. Furthermore, we explore RNH1 as a therapeutic target in sepsis-related processes like inflammation, non-canonical inflammasome activation, and iron homeostasis. We showed that RNH1 levels are significantly higher in deceased patients compared to sepsis survivors and correlate with creatine kinase, aspartate and alanine transaminase, bilirubin, serum creatinine and RNase 5, but not RNase 1. RNH1 mitigated LPS-induced TNFα and RNase 5 secretion, and relative mRNA expression of ferroptosis-associated genes HMOX1, FTH1 and HAMP in PBMCs. Monocytes were identified as the predominant type of LPS-positive PBMCs. Exogenous RNH1 attenuated LPS-induced CASP5 expression, while increasing IL-1β secretion in PBMCs and THP-1 macrophages. As RNH1 has contradictory effects on inflammation and non-canonical inflammasome activation, its use as a therapeutic agent is limited. However, RNH1 levels may play a central role in iron homeostasis during sepsis, supporting our clinical observations. Hence, RNH1 shows promise as biomarkers for renal and hepatic dysfunction and hepatocyte injury, and may be useful in predicting the outcome of septic patients.
10.1038/s41598-024-65778-8
Targeting ferroptosis protects against experimental (multi)organ dysfunction and death.
Nature communications
The most common cause of death in the intensive care unit (ICU) is the development of multiorgan dysfunction syndrome (MODS). Besides life-supporting treatments, no cure exists, and its mechanisms are still poorly understood. Catalytic iron is associated with ICU mortality and is known to cause free radical-mediated cellular toxicity. It is thought to induce excessive lipid peroxidation, the main characteristic of an iron-dependent type of cell death conceptualized as ferroptosis. Here we show that the severity of multiorgan dysfunction and the probability of death are indeed associated with plasma catalytic iron and lipid peroxidation. Transgenic approaches underscore the role of ferroptosis in iron-induced multiorgan dysfunction. Blocking lipid peroxidation with our highly soluble ferrostatin-analogue protects mice from injury and death in experimental non-septic multiorgan dysfunction, but not in sepsis-induced multiorgan dysfunction. The limitations of the experimental mice models to mimic the complexity of clinical MODS warrant further preclinical testing. In conclusion, our data suggest ferroptosis targeting as possible treatment option for a stratifiable subset of MODS patients.
10.1038/s41467-022-28718-6
Heme: The Lord of the Iron Ring.
Antioxidants (Basel, Switzerland)
Heme is an iron-protoporphyrin complex with an essential physiologic function for all cells, especially for those in which heme is a key prosthetic group of proteins such as hemoglobin, myoglobin, and cytochromes of the mitochondria. However, it is also known that heme can participate in pro-oxidant and pro-inflammatory responses, leading to cytotoxicity in various tissues and organs such as the kidney, brain, heart, liver, and in immune cells. Indeed, heme, released as a result of tissue damage, can stimulate local and remote inflammatory reactions. These can initiate innate immune responses that, if left uncontrolled, can compound primary injuries and promote organ failure. In contrast, a cadre of heme receptors are arrayed on the plasma membrane that is designed either for heme import into the cell, or for the purpose of activating specific signaling pathways. Thus, free heme can serve either as a deleterious molecule, or one that can traffic and initiate highly specific cellular responses that are teleologically important for survival. Herein, we review heme metabolism and signaling pathways, including heme synthesis, degradation, and scavenging. We will focus on trauma and inflammatory diseases, including traumatic brain injury, trauma-related sepsis, cancer, and cardiovascular diseases where current work suggests that heme may be most important.
10.3390/antiox12051074
METTL4 mediated-N6-methyladenosine promotes acute lung injury by activating ferroptosis in alveolar epithelial cells.
Free radical biology & medicine
Sepsis-induced acute lung injury has been deemed to be an life-threatening pulmonary dysfunction caused by a dysregulated host response to infection. The modification of N6-Methyladenosine (m6A) is implicated in several biological processes, including mitochondrial transcription and ferroptosis. Ferroptosis is an iron-dependent type of programed cell death, which plays a role in sepsis-induced acute lung injury (ALI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of intracellular oxidative homeostasis, linked to ferroptosis resistance. This research aims to explore the effect of m6A in ferroptosis in sepsis-induced ALI. First, we found a time-dependent dynamic alteration on pulmonary methylation level during sepsis-induced ALI. We identified METTL4 as a differentially expressed gene in ALI mice using m6A sequencing and RNA-sequencing, and revealed the methylation of several ferroptosis related genes (Nrf2). Thus, we generated METTL4 deficiency mice and found that METTL4 knockdown alleviated ferroptosis, as evidenced by lipid ROS, MDA, Fe, as well as alterations in GPX4 and SLC7A11 protein expression. Consistently, we found that METTL4 silencing could decrease ferroptosis sensitivity in LPS-induced TC-1 cells. Furthermore, both the dual-luciferase reporter assay and rescue experiments indicated that METTL4 mediated the N6-methyladenosine of Nrf2 3'UTR, then YTHDF2 binded with the m6A site, promoting the degradation of Nrf2. In conclusion, we revealed that METTL4 promoted alveolar epithelial cells ferroptosis in sepsis-induced lung injury via N6-methyladenosine of Nrf2, which might provide a novel approach to therapeutic strategies for sepsis-induced ALI.
10.1016/j.freeradbiomed.2024.01.013
Engineered Extracellular Vesicles Driven by Erythrocytes Ameliorate Bacterial Sepsis by Iron Recycling, Toxin Clearing and Inflammation Regulation.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Sepsis poses a significant challenge in clinical management. Effective strategies targeting iron restriction, toxin neutralization, and inflammation regulation are crucial in combating sepsis. However, a comprehensive approach simultaneously targeting these multiple processes has not been established. Here, an engineered apoptotic extracellular vesicles (apoEVs) derived from macrophages is developed and their potential as multifunctional agents for sepsis treatment is investigated. The extensive macrophage apoptosis in a Staphylococcus aureus-induced sepsis model is discovered, unexpectedly revealing a protective role for the host. Mechanistically, the protective effects are mediated by apoptotic macrophage-released apoEVs, which bound iron-containing proteins and neutralized α-toxin through interaction with membrane receptors (transferrin receptor and A disintegrin and metalloprotease 10). To further enhance therapeutic efficiency, apoEVs are engineered by incorporating mesoporous silica nanoparticles preloaded with anti-inflammatory agents (microRNA-146a). These engineered apoEVs can capture iron and neutralize α-toxin with their natural membrane while also regulating inflammation by releasing microRNA-146a in phagocytes. Moreover, to exploit the microcosmic movement and rotation capabilities, erythrocytes are utilized to drive the engineered apoEVs. The erythrocytes-driven engineered apoEVs demonstrate a high capacity for toxin and iron capture, ultimately providing protection against sepsis associated with high iron-loaded conditions. The findings establish a multifunctional agent that combines natural and engineered antibacterial strategies.
10.1002/advs.202306884
Knockdown of LncRNA Lcn2-204 alleviates sepsis-induced myocardial injury by regulation of iron overload and ferroptosis.
Journal of molecular and cellular cardiology
Ferroptosis is an iron-dependent programmed cell death form resulting from lipid peroxidation damage, it plays a key role in organ damage and tumor development from various causes. Sepsis leads to severe host response after infection with high mortality. The long non-coding RNAs (LncRNAs) are involved in different pathophysiological mechanisms of multiple diseases. Here, we used cecal ligation and puncture (CLP) operation to mimic sepsis induced myocardial injury (SIMI) in mouse model, and LncRNAs and mRNAs were profiled by Arraystar mouse LncRNA Array V3.0. Based on the microarray results, 552 LncRNAs and 520 mRNAs were differentially expressed in the sham and CLP groups, among them, LncRNA Lcn2-204 was the highest differentially expressed up-regulated LncRNA. Iron metabolism disorder was involved in SIMI by bioinformatics analysis, meanwhile, myocardial iron content and lipocalin-2 (Lcn2) protein expressions were increased. The CNC network comprised 137 positive interactions and 138 negative interactions. Bioinformatics analysis showed several iron-related terms were enriched and six genes (Scara5, Tfrc, Lcn2, Cp, Clic5, Ank1) were closely associated with iron metabolism. Then, we constructed knockdown LncRNA Lcn2-204 targeting myocardium and found that it ameliorated cardiac injury in mouse sepsis model through modulating iron overload and ferroptosis. In addition, we found that LncRNA Lcn2-204 was involved in the regulation of Lcn2 expression in septic myocardial injury. Based on these findings, we conclude that iron overload and ferroptosis are the key mechanisms leading to myocardial injury in sepsis, knockdown of LncRNA Lcn2-204 plays the cardioprotective effect through inhibition of iron overload, ferroptosis and Lcn2 expression. It may provide a novel therapeutic approach to ameliorate sepsis-induced myocardial injury.
10.1016/j.yjmcc.2024.05.007
Effects of Tocilizumab on Inflammation and Iron Metabolism in Critically Ill Patients with COVID-19.
Pharmaceutics
COVID-19 produces cytokine-mediated persistent inflammation and is associated with elevated iron stores and low circulating iron. It is believed that central to the pathophysiological mechanism is interleukin 6 and hepcidin. A state of iron overload, termed hyperferritinemia, and inflammatory anemia take place. Both conditions are linked to a worse result in critically ill patients. Blocking the interleukin 6-hepcidin pathway with Tocilizumab could present favorable outcomes. The aim of this study was to evaluate if Tocilizumab influences survival, the occurrence of sepsis, anemia and transfusions in critically ill patients suffering from COVID-19. This prospective observational study focused on levels of interleukin 6, hepcidin and blood iron parameters in patients treated with Tocilizumab. Data were compared before and after therapy as well as between treated and control groups. Results indicate that there is no difference in terms of survival nor in the rate of anemia or sepsis occurrence. Hepcidin was elevated and anemia ensued after treatment, which could indicate alternative pathways. In conclusion, when the classic interleukin 6-hepcidin pathway is blocked, inflammation seems to use alternative routes. Further understanding of these pathways is required and new pharmacological therapies need to be developed to treat persistent inflammation.
10.3390/pharmaceutics15020646
Humoral regulation of iron metabolism by extracellular vesicles drives antibacterial response.
Nature metabolism
Immediate restriction of iron initiated by the host is a critical process to protect against bacterial infections and has been described in the liver and spleen, but it remains unclear whether this response also entails a humoral mechanism that would enable systemic sequestering of iron upon infection. Here we show that upon bacterial invasion, host macrophages immediately release extracellular vesicles (EVs) that capture circulating iron-containing proteins. Mechanistically, in a sepsis model in female mice, Salmonella enterica subsp. enterica serovar Typhimurium induces endoplasmic reticulum stress in macrophages and activates inositol-requiring enzyme 1α signaling, triggering lysosomal dysfunction and thereby promoting the release of EVs, which bear multiple receptors required for iron uptake. By binding to circulating iron-containing proteins, these EVs prevent bacteria from iron acquisition, which inhibits their growth and ultimately protects against infection and related tissue damage. Our findings reveal a humoral mechanism that can promptly regulate systemic iron metabolism during bacterial infection.
10.1038/s42255-022-00723-5
Protection of zero-valent iron nanoparticles against sepsis and septic heart failure.
Journal of nanobiotechnology
BACKGROUND:Septic heart failure accounts for high mortality rates globally. With a strong reducing capacity, zero-valent iron nanoparticles (nanoFe) have been applied in many fields. However, the precise roles and mechanisms of nanoFe in septic cardiomyopathy remain unknown. RESULTS:NanoFe was prepared via the liquid-phase reduction method and functionalized with the biocompatible polymer sodium carboxymethylcellulose (CMC). We then successfully constructed a mouse model of septic myocardial injury by challenging with cecal ligation and puncture (CLP). Our findings demonstrated that nanoFe has a significant protective effect on CLP-induced septic myocardial injury. This may be achieved by attenuating inflammation and oxidative stress, improving mitochondrial function, regulating endoplasmic reticulum stress, and activating the AMPK pathway. The RNA-seq results supported the role of nanoFe treatment in regulating a transcriptional profile consistent with its role in response to sepsis. CONCLUSIONS:The results provide a theoretical basis for the application strategy and combination of nanoFe in sepsis and septic myocardial injury.
10.1186/s12951-022-01589-1
Iron status and the risk of sepsis and severe COVID-19: a two-sample Mendelian randomization study.
Scientific reports
Observational studies have indicated an association between iron status and risk of sepsis and COVID-19. We estimated the effect of genetically-predicted iron biomarkers on risk of sepsis and risk of being hospitalized with COVID-19, performing a two-sample Mendelian randomization study. For risk of sepsis, one standard deviation increase in genetically-predicted serum iron was associated with odds ratio (OR) of 1.14 (95% confidence interval [CI] 1.01-1.29, P = 0.031). The findings were supported in the analyses for transferrin saturation and total iron binding capacity, while the estimate for ferritin was inconclusive. We found a tendency of higher risk of hospitalization with COVID-19 for serum iron; OR 1.29 (CI 0.97-1.72, P = 0.08), whereas sex-stratified analyses showed OR 1.63 (CI 0.94-2.86, P = 0.09) for women and OR 1.21 (CI 0.92-1.62, P = 0.17) for men. Sensitivity analyses supported the main findings and did not suggest bias due to pleiotropy. Our findings suggest a causal effect of genetically-predicted higher iron status and risk of hospitalization due to sepsis and indications of an increased risk of being hospitalized with COVID-19. These findings warrant further studies to assess iron status in relation to severe infections, including the potential of improved management.
10.1038/s41598-022-20679-6
Molecular Mechanisms of Ferroptosis and Their Involvement in Acute Kidney Injury.
Journal of inflammation research
Ferroptosis is a novel way of regulating cell death, which occurs in a process that is closely linked to intracellular iron metabolism, lipid metabolism, amino acid metabolism, and multiple signaling pathways. The latest research shows that ferroptosis plays a key role in the pathogenesis of acute kidney injury (AKI). Ferroptosis may be an important target for treating AKI caused by various reasons, such as ischemia-reperfusion injury, rhabdomyolysis syndrome, sepsis, and nephrotoxic drugs. This paper provides a review on the regulatory mechanisms of ferroptosis and its role in AKI, which may help to provide new research ideas for the treatment of AKI and future research.
10.2147/JIR.S427505
Iron Metabolism in the Recovery Phase of Critical Illness with a Focus on Sepsis.
International journal of molecular sciences
Iron is an essential nutrient for humans and microbes, such as bacteria. Iron deficiency commonly occurs in critically ill patients, but supplementary iron therapy is not considered during the acute phase of critical illness since it increases iron availability for invading microbes and oxidative stress. However, persistent iron deficiency in the recovery phase is harmful and has potential adverse outcomes such as cognitive dysfunction, fatigue, and cardiopulmonary dysfunction. Therefore, it is important to treat iron deficiency quickly and efficiently. This article reviews current knowledge about iron-related biomarkers in critical illness with a focus on patients with sepsis, and provides possible criteria to guide decision-making for iron supplementation in the recovery phase of those patients.
10.3390/ijms25137004
Cross-Talk Between Iron and Glucose Metabolism in the Establishment of Disease Tolerance.
Carlos Ana Rita,Weis Sebastian,Soares Miguel P
Frontiers in immunology
Infectious diseases are associated with disruption of host homeostasis. This can be triggered directly by pathogens or indirectly by host immune-driven resistance mechanisms. Disease tolerance is a defense strategy against infection that sustains host homeostasis, without exerting a direct negative impact on pathogens. The mechanisms governing disease tolerance encompass host metabolic responses that maintain vital homeostatic parameters within a range compatible with survival. Central to this defense strategy is the host's ability to sense and adapt to variations in nutrients, such as iron and glucose. Here we address how host responses regulating iron and glucose metabolism interact to establish disease tolerance and possibly modulate resistance to infection.
10.3389/fimmu.2018.02498
Sestrin2 protects dendrite cells against ferroptosis induced by sepsis.
Cell death & disease
Ferroptosis is a nonapoptotic form of programmed cell death triggered by the accumulation of reactive oxygen species (ROS) depended on iron overload. Although most investigations focus on the relationship between ferroptosis and cancer, neurodegenerative diseases, and ischemia/reperfusion injury, research on ferroptosis induced by immune-related inflammatory diseases, especially sepsis, is scarce. Sestrin2 (Sesn2), a highly evolutionary and stress-responsive protein, is critically involved in defense against oxidative stress challenges. Upregulated expression of Sesn2 has been observed in preliminary experiments to have an antioxidative function in the context of an inflammatory response. Nevertheless, the underlying function of Sesn2 in inflammation-mediated ferroptosis in the immune system remains uncertain. The current study aimed to demonstrate the protective effect of Sesn2 on ferroptosis and even correlations with ferroptosis and the functions of ferroptotic-dendritic cells (DCs) stimulated with lipopolysaccharide (LPS). The mechanism underlying DCs protection from LPS-induced ferroptosis by Sesn2 was further explored in this study. We found that the immune response of DCs assessed by co-stimulatory phenotypes was gradually enhanced at the peak time of 12 h upon 1 μg/ml LPS stimulation while ferroptosis in DCs treated with LPS at 24 h was significantly detected. LPS-induced ferroptosis showed a suppressive impact on DCs in phenotypic maturation, which was conversely relieved by the ferroptotic inhibitor. Compared with wild-type (WT) mice, DCs in genetic defective mice of Sesn2 (Sesn2) exhibited exacerbated ferroptosis. Furthermore, the protective effect of Sesn2 on ferroptosis was noticed to be associated with the ATF4-CHOP-CHAC1 pathway, eventually exacerbating ferroptosis by degrading of glutathione. These results indicate that Sesn2 can suppress the ferroptosis of DCs in sepsis by downregulating the ATF4-CHOP-CHAC1 signaling pathway, and it might play an antioxidative role.
10.1038/s41419-021-04122-8
Iron Homeostasis and Ferritin in Sepsis-Associated Kidney Injury.
Nephron
Sepsis associated acute kidney injury (SA-AKI) is a common clinical syndrome that occurs among hospitalized patients and significantly impacts mortality. Furthermore, survival after sepsis is intricately dependent on recovery of kidney function. In this review, we discuss the role of iron imbalance in mediating the pathogenic events during sepsis. Intracellular ferritin serves as a repository for iron and prevents iron-mediated injury and may limit the availability of iron to pathogens. Circulating levels of ferritin also increase during sepsis and often correlate with severity of sepsis. Herein, we examine preclinical and clinical data and discuss recent findings that suggest immunomodulatory roles for ferritin. We also discuss the possible mechanistic roles for ferritin in mitigating the pathogenic sequelae of sepsis and highlight current gaps in knowledge.
10.1159/000508857
The Role of Iron Metabolism in Sepsis-associated Encephalopathy: a Potential Target.
Molecular neurobiology
Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction secondary to infection, and the severity can range from mild delirium to deep coma. Disorders of iron metabolism have been proven to play an important role in a variety of neurodegenerative diseases by inducing cell damage through iron accumulation in glial cells and neurons. Recent studies have found that iron accumulation is also a potential mechanism of SAE. Systemic inflammation can induce changes in the expression of transporters and receptors on cells, especially high expression of divalent metal transporter1 (DMT1) and low expression of ferroportin (Fpn) 1, which leads to iron accumulation in cells. Excessive free Fe can participate in the Fenton reaction to produce reactive oxygen species (ROS) to directly damage cells or induce ferroptosis. As a result, it may be of great help to improve SAE by treatment of targeting disorders of iron metabolism. Therefore, it is important to review the current research progress on the mechanism of SAE based on iron metabolism disorders. In addition, we also briefly describe the current status of SAE and iron metabolism disorders and emphasize the therapeutic prospect of targeting iron accumulation as a treatment for SAE, especially iron chelator. Moreover, drug delivery and side effects can be improved with the development of nanotechnology. This work suggests that treating SAE based on disorders of iron metabolism will be a thriving field.
10.1007/s12035-023-03870-2
Iron homeostasis and disorders revisited in the sepsis.
Liu Qinjie,Wu Jie,Zhang Xufei,Wu Xiuwen,Zhao Yun,Ren Jianan
Free radical biology & medicine
Sepsis is a life-threatening condition caused by a dysregulated host-response to inflammation, although it currently lacks a fully elucidated pathobiology. Iron is a crucial trace element that is essential for fundamental processes in both humans and bacteria. During sepsis, iron metabolism is altered, including increased iron transport and uptake into cells and decreased iron export. The intracellular sequestration of iron limits its availability to circulating pathogens, which serves as a conservative strategy against the pathogens. Although iron retention has been showed to have protective protect effects, an increase in labile iron may cause oxidative injury and cell death (e.g., pyroptosis, ferroptosis) as the condition progresses. Moreover, iron disorders are substantial and correlate with the severity of sepsis. This also suggests that iron may be useful as a diagnostic marker for evaluating the severity and predicting the outcome of the disease. Further knowledge about these disorders could help in evaluating how drugs targeting iron homeostasis can be optimally applied to improve the treatment of patients with sepsis. Here, we present a comprehensive review of recent advances in the understanding of iron metabolism, focusing on the regulatory mechanisms and iron-mediated injury in sepsis.
10.1016/j.freeradbiomed.2021.01.025
Ferroptosis: principles and significance in health and disease.
Journal of hematology & oncology
Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed by molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic cell death pathway in 2012, ferroptosis has emerged as a crucial mechanism in numerous physiological and pathological contexts, leading to significant therapeutic advancements across a wide range of diseases. This review summarizes the fundamental molecular mechanisms and regulatory pathways underlying ferroptosis, including both GPX4-dependent and -independent antioxidant mechanisms. Additionally, we examine the involvement of ferroptosis in various pathological conditions, including cancer, neurodegenerative diseases, sepsis, ischemia-reperfusion injury, autoimmune disorders, and metabolic disorders. Specifically, we explore the role of ferroptosis in response to chemotherapy, radiotherapy, immunotherapy, nanotherapy, and targeted therapy. Furthermore, we discuss pharmacological strategies for modulating ferroptosis and potential biomarkers for monitoring this process. Lastly, we elucidate the interplay between ferroptosis and other forms of regulated cell death. Such insights hold promise for advancing our understanding of ferroptosis in the context of human health and disease.
10.1186/s13045-024-01564-3
DTPA Fe(III) decreases cytokines and hypotension but worsens survival with Escherichia coli sepsis in rats.
Li Yan,Li Xuemei,Haley Michael,Fitz Yvonne,Gerstenberger Eric,Banks Steven M,Eichacker Peter Q,Cui Xizhong
Intensive care medicine
OBJECTIVE:Nonselective inhibition of nitric oxide (NO) with NO synthase antagonists decreases hypotension but worsens outcome clinically. We investigated whether iron (III) complex of diethylenetriaminepentaacetic acid [DTPA Fe(III)], a scavenger of NO as well as other oxidant mediators, has similar divergent effects in E. coli challenged rats. METHODS:Animals with venous and arterial catheters and challenged with intrabronchial or intravenous E. coli were randomized to treatment with DTPA Fe(III) in doses from 3 to 800 mg/kg or placebo. Mean blood pressure (MBP) was measured in all animals and plasma NO, cytokines, and blood and lung leukocyte and bacteria counts in animals administered intrabronchial E. coli and DTPA Fe(III) 50 mg/kg or placebo. Animals received antibiotics and were observed 168 h. RESULTS:Independent of drug regimen or infection site, compared to placebo, DTPA Fe(III) increased MBP although this was greater with high vs. lower doses. Despite increased MBP, DTPA Fe(III) worsened the hazards ratio of survival . At 6 and 24 h DTPA Fe(III) decreased NO but not significantly and decreased four cytokines (tumor necrosis factor-alpha, interleukins 1 and 10, and macrophage inflammatory protein 3alpha) and lung lavage neutrophils. From 6 to 24 h DTPA Fe(III) increased blood bacteria. CONCLUSIONS:DTPA Fe(III) while increasing blood pressure has the potential to worsen outcome in sepsis. Further preclinical testing is required before this agent is applied clinically.
10.1007/s00134-006-0234-2
Association of iron status with the risk of bloodstream infections: results from the prospective population-based HUNT Study in Norway.
Mohus Randi Marie,Paulsen Julie,Gustad Lise,Askim Åsa,Mehl Arne,DeWan Andrew T,Afset Jan Egil,Åsvold Bjørn Olav,Solligård Erik,Damås Jan Kristian
Intensive care medicine
PURPOSE:As iron is essential for both immune function and microbial growth, alterations in iron status could influence the risk of infections. We assessed the associations of iron status with risk of bloodstream infections (BSIs) and BSI mortality. METHODS:We measured serum iron, transferrin saturation (Tsat) and total iron-binding capacity (TIBC) in 61,852 participants in the population-based HUNT2 study (1995-97). Incident BSIs (1995-2011) were identified through linkage with the Mid-Norway Sepsis Register, which includes prospectively registered information on BSI from local and regional hospitals. We assessed the risk of a first-time BSI and BSI mortality with the iron indices using Cox proportional hazards regression analysis. RESULTS:During a median follow-up of 14.8 years, 1738 individuals experienced at least one episode of BSI, and 370 died within 30 days after a BSI. In age- and sex-adjusted analyses, BSI risk was increased among participants with indices of iron deficiency, serum iron ≤ 2.5th percentile (HR 1.72, 95% CI 1.34-2.21), Tsat ≤ 2.5th percentile (HR 1.48, 95% CI 1.12-1.96) or TIBC ≥ 97.5th percentile (HR 1.46, 95% CI 1.06-2.01). The associations remained similar after adjusting for comorbidities and exclusion of BSI related to cancer, rheumatic illnesses and inflammatory bowel disease. BSI mortality showed similar associations. CONCLUSION:Indices of severe iron deficiency are associated with an increased risk of a future BSI.
10.1007/s00134-018-5320-8
Iron status following trauma, excluding burns.
Walsh D S,Pattanapanyasat K,Lamchiagdhase P,Siritongtaworn P,Thavichaigarn P,Jiarakul N,Chuntrasakul C,Komoltri C,Dheeradhada C,Pearce F C,Wiesmann W P,Webster H K
The British journal of surgery
Serum concentration of iron, transferrin saturation and total iron binding capacity (TIBC) were measured on days 1, 2, 3, 5, 7, 10 and 13 in 36 Thai patients with trauma (burns excluded) to determine temporal changes in iron metabolism. Throughout the study profound hypoferraemia was observed in association with decreased transferrin saturation. TIBC, in contrast, did not differ significantly from that in controls. These findings confirm previous reports which describe altered iron metabolism in association with an adverse event, a response known as 'stress hypoferraemia', and extends these observations to non-burned patients with trauma. The degree of hypoferraemia in patients in this study was not related to sepsis, Injury Severity Score, volume of blood transfused or surgery, suggesting that hypoferraemia following trauma is an independent event. The recognition of rapid and prolonged iron sequestration provides insight into the clinical condition of patients with trauma.
10.1002/bjs.1800830731
Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia.
Holden Victoria I,Breen Paul,Houle Sébastien,Dozois Charles M,Bachman Michael A
mBio
UNLABELLED:Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro, siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia. IMPORTANCE:Klebsiella pneumoniae causes a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection, K. pneumoniae steals iron from its host by secreting siderophores, small iron-chelating molecules. Classically, siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secreting K. pneumoniae causes lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secreting K. pneumoniae activates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection with K. pneumoniae Together, these results indicate that bacterial siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of siderophores could provide a two-pronged attack against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood.
10.1128/mBio.01397-16
The VDR/FFAR2 axis mitigates sepsis-induced lung injury by suppressing macrophage lipid peroxidation.
International immunopharmacology
Sepsis-induced lung injury is a common critical condition in clinical practice, characterized by the accumulation of peroxides and inflammatory damage caused by excessive macrophage activation. Currently, effective treatments for sepsis-induced lung injury are lacking. Short-chain fatty acid receptor FFAR2 serves as an anti-inflammatory biomarker, but its role and mechanism in sepsis-induced lung injury remain unclear. To elucidate the influence and mechanism of FFAR2 on macrophage lipid peroxidation levels in sepsis-induced lung injury, this study conducted bioinformatics analysis and cellular experiments using the THP-1 macrophage cell line. By dual luciferase reporter and chromatin immunoprecipitation-quantitative PCR assays, it is confirmed that the transcription factor VDR upregulates FFAR2 expression in macrophages by binding to the promoter region -1695 ∼ 1525, thereby increasing the expression of iron death negative regulatory molecules and lowering macrophage lipid peroxidation levels. Moreover, both in vitro using THP-1 cells and bone marrow-derived macrophages (BMDMs) and in vivo using an LPS-induced septic mice model experiments revealed that activating the VDR/FFAR2 axis could reduce inflammation-induced macrophage lipid peroxide accumulation and alleviate lung injury in septic mice. This finding highlights the potential of FFAR2 as an immunotherapeutic target for mitigating sepsis-related lung injury.
10.1016/j.intimp.2024.113328
Parenteral iron therapy exacerbates experimental sepsis.
Zager Richard A,Johnson Ali C M,Hanson Sherry Y
Kidney international
BACKGROUND:Catalytic iron can potentiate systemic inflammation via its pro-oxidant effects. This raises the possibility that parenteral iron administration might exacerbate a concomitant septic state. This study sought to experimentally test this hypothesis. METHODS:Male CD-1 mice were subjected to experimental sepsis via intraperitoneal injection of heat-killed Escherichia coli +/- concomitant intravenous iron sucrose (Venofer; 2 mg). Nonseptic mice +/- iron therapy served as controls. Plasma tumor necrosis factor-alpha (TNF-alpha) levels were assessed 2 hours postinjections (serving as an inflammatory marker). Oxidative stress was gauged in heart or kidney tissue (at either 4 or 24 hours) by heme oxygenase-1 (HO-1) mRNA or protein levels. Overall sepsis severity was assessed by morbidity/mortality rates (at 24 hours). RESULTS:Iron alone or sepsis alone each induced oxidant stress in heart and kidney (HO-1 mRNA/protein increases). When iron and E. coli were coadministered, additive or synergistic HO-1 mRNA/protein increments resulted. Iron injection alone only slightly raised TNF-alpha levels (from 0 to 2.3 pg/mL; P= 0.01). However, iron approximately doubled the TNF-alpha increments which arose from the septic state (1400 --> 2600 pg/mL). Neither sepsis alone, nor iron alone, induced any mortality and no mice became moribund (0/24 mice). However, when iron + sepsis were combined, approximately 60% of mice either died (5/12) or developed a moribund (2/12) state (P= 0.005). CONCLUSION:Parenteral iron administration can induce systemic oxidative stress and modest TNF-alpha release. However, when iron is given during experimental sepsis, profound increases in both processes, and approximately 60% mortality, result. Given that renal failure patients have decreased antioxidant defenses and intermittently develop bacteremia, the potential for parenteral iron therapy to exacerbate clinical sepsis needs to be addressed.
10.1111/j.1523-1755.2004.00742.x
Serum ferritin levels in inflammation: a retrospective comparative analysis between COVID-19 and emergency surgical non-COVID-19 patients.
World journal of emergency surgery : WJES
BACKGROUND:SARS-CoV-2 infection has spread worldwide, and the pathogenic mechanism is still under investigation. The presence of a huge inflammatory response, defined as "cytokine storm," is being studied in order to understand what might be the prognostic factors implicated in the progression of the infection, with ferritin being one of such markers. The role of ferritin as a marker of inflammation is already known, and whether it changes differently between COVID and non-COVID patients still remains unclear. The aim of this retrospective analysis is to understand whether the inflammatory process in these two types is different. METHODS:In this retrospective analysis, we compared 17 patients affected by SARS-CoV-2, who had been admitted between February and April 2020 (group A) along with 30 patients admitted for acute surgical disease with SARS-CoV-2 negative swab (group B). A further subgroup of Covid negative patients with leukocytosis was compared to group A. RESULTS:In group A, the median (interquartile range) serum ferritin was 674 (1284) ng/mL, and it was double the cutoff (300 ng/mL) in 9 out of 17 (52%). The median (IQR) value of ferritin level in the total blood samples of group B was 231, and in the subgroup with leucocytosis, 149 (145). Group A showed a significantly higher ferritin median level compared to the entire group B (two-tailed Mann-Whitney test, p < 0.0001) as well as to the subgroup with leucocytosis (p < 0.0014). CONCLUSIONS:The role of iron metabolism appears to be directly involved in COVID infection. On the other hand, in the acute inflammation of patients admitted for surgery, and probably in other common phlogistic processes, iron modifications appear to be self-limited. However, our finding suggests the use of ferritin as a marker for COVID infection.
10.1186/s13017-021-00354-3
The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study.
Markousis-Mavrogenis George,Tromp Jasper,Ouwerkerk Wouter,Devalaraja Matt,Anker Stefan D,Cleland John G,Dickstein Kenneth,Filippatos Gerasimos S,van der Harst Pim,Lang Chim C,Metra Marco,Ng Leong L,Ponikowski Piotr,Samani Nilesh J,Zannad Faiez,Zwinderman Aeilko H,Hillege Hans L,van Veldhuisen Dirk J,Kakkar Rahul,Voors Adriaan A,van der Meer Peter
European journal of heart failure
AIMS:Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)-α were largely unsuccessful. Interleukin (IL)-6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL-6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. METHODS AND RESULTS:Interleukin-6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT-CHF cohort. The primary outcome was all-cause mortality and HF hospitalization during 2 years, with all-cause, cardiovascular (CV), and non-CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL-6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N-terminal pro-brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF-α/IL-1-related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL-6 levels. IL-6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11-1.21), P < 0.001], all-cause mortality [1.22 (1.16-1.29), P < 0.001] and CV as well as non-CV mortality [1.16 (1.09-1.24), P < 0.001; 1.31 (1.18-1.45), P < 0.001], but did not improve discrimination in previously published risk models. CONCLUSIONS:In a large, heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL-6 as a potential therapeutic target in specific HF subpopulations.
10.1002/ejhf.1482
Iron and platelets: A subtle, under-recognized relationship.
Brissot Eolia,Troadec Marie-Bérengère,Loréal Olivier,Brissot Pierre
American journal of hematology
The role of iron in the formation and functioning of erythrocytes, and to a lesser degree of white blood cells, is well established, but the relationship between iron and platelets is less documented. Physiologically, iron plays an important role in hematopoiesis, including thrombopoiesis; iron levels direct, together with genetic factors, the lineage commitment of megakaryocytic/erythroid progenitors toward either megakaryocyte or erythroid progenitors. Megakaryocytic iron contributes to cellular machinery, especially energy production in platelet mitochondria. Thrombocytosis, possibly favoring vascular thrombosis, is a classical feature observed with abnormally low total body iron stores (mainly due to blood losses or decreased duodenal iron intake), but thrombocytopenia can also occur in severe iron deficiency anemia. Iron sequestration, as seen in inflammatory conditions, can be associated with early thrombocytopenia due to platelet consumption and followed by reactive replenishment of the platelet pool with possibility of thrombocytosis. Iron overload of genetic origin (hemochromatosis), despite expected mitochondrial damage related to ferroptosis, has not been reported to cause thrombocytopenia (except in case of high degree of hepatic fibrosis), and iron-related alteration of platelet function is still a matter of debate. In acquired iron overload (of transfusional and/or dyserythropoiesis origin), quantitative or qualitative platelet changes are difficult to attribute to iron alone due to the interference of the underlying hematological conditions; likewise, hematological improvement, including increased blood platelet counts, observed under iron oral chelation is likely to reflect mechanisms other than the sole beneficial impact of iron depletion.
10.1002/ajh.26189