Research advances in pathogenesis and prophylactic measures of acute high altitude illness.
Li Yunhong,Zhang Yujing,Zhang Ying
Respiratory medicine
After ascent to high altitude (≥2500 m), the inability of the human body to adapt to the hypobaric and hypoxia environment can induce tissue hypoxia, then a series of high altitude illnesses including acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) would develop. Symptoms of AMS include headache, dizziness, nausea, and vomiting; HAPE is characterized by orthopnea, breathlessness at rest, cough, pink frothy sputum, and results in obvious pulmonary edema that poses significant harm to people; HACE is characterized by ataxia and decreased consciousness, leading to coma and brain herniation which would be fatal if not treated promptly. This review article provides a current understanding of the pathophysiology of these three forms of high altitude illness and elaborates the current prevention and treatment measures of these diseases.
10.1016/j.rmed.2018.11.004
A bioactive gypenoside (GP-14) alleviates neuroinflammation and blood brain barrier (BBB) disruption by inhibiting the NF-κB signaling pathway in a mouse high-altitude cerebral edema (HACE) model.
International immunopharmacology
BACKGROUND:Neuroinflammation caused by peripheral lipopolysaccharides (LPS) under hypoxia is a key contributor to the development of high altitude cerebral edema (HACE). Our previous studies have shown that gypenosides and their bioactive compounds prevent hypoxia-induced neural injuries in vitro and in vivo. However, their effect on neuroinflammation-related HACE remains to be illustrated. The present study aimed to investigate the effects of GP-14 in HACE mouse model. METHODS:HACE mice were treated with GP-14 (100 and 200 mg/kg) for 7 days. After the treatments, the level of serum inflammation cytokines and the transcription of inflammatory factors in brain tissue were determined. The activation of microglia, astrocyte and the changes of IgG leakage and the protein levels of tight junction proteins were detected. Furthermore, the inflammatory factors and nuclear factor-κB (NF-κB) signaling pathway in BV-2 cells and primary microglia were detected. RESULTS:GP-14 pretreatment alleviated both the serum and neural inflammatory responses caused by LPS stimulation combined with hypobaric hypoxia exposure. In addition, GP-14 pretreatment inhibited microglial activation, accompanied by a decrease in the M1 phenotype and an increase in the M2 phenotype. Moreover, the disruption of the blood brain barrier (BBB) integrity, including increased IgG leakage and decreased expression of tight junction proteins, was attenuated by GP-14 pretreatment. Based on the BV-2 and primary microglial models, the inflammatory response and activation of the NF-κB signaling pathway were also inhibited by GP-14 pretreatment. CONCLUSION:Taken together, our results demonstrated that GP-14 exhibited prominent protective roles against neuroinflammation and BBB disruption in a mouse HACE model. GP-14 could be a potential choice for the treatment of HACE in the future.
10.1016/j.intimp.2022.108675
High-altitude illnesses: Old stories and new insights into the pathophysiology, treatment and prevention.
Sports medicine and health science
Areas at high-altitude, annually attract millions of tourists, skiers, trekkers, and climbers. If not adequately prepared and not considering certain ascent rules, a considerable proportion of those people will suffer from acute mountain sickness (AMS) or even from life-threatening high-altitude cerebral (HACE) or/and pulmonary edema (HAPE). Reduced inspired oxygen partial pressure with gain in altitude and consequently reduced oxygen availability is primarily responsible for getting sick in this setting. Appropriate acclimatization by slowly raising the hypoxic stimulus (e.g., slow ascent to high altitude) and/or repeated exposures to altitude or artificial, normobaric hypoxia will largely prevent those illnesses. Understanding physiological mechanisms of acclimatization and pathophysiological mechanisms of high-altitude diseases, knowledge of symptoms and signs, treatment and prevention strategies will largely contribute to the risk reduction and increased safety, success and enjoyment at high altitude. Thus, this review is intended to provide a sound basis for both physicians counseling high-altitude visitors and high-altitude visitors themselves.
10.1016/j.smhs.2021.04.001
Progress in the Treatment of High Altitude Cerebral Edema: Targeting REDOX Homeostasis.
Journal of inflammation research
With the increasing of altitude activities from low-altitude people, the study of high altitude cerebral edema (HACE) has been revived. HACE is a severe acute mountain sickness associated with exposure to hypobaric hypoxia at high altitude, often characterized by disturbance of consciousness and ataxia. As for the pathogenesis of HACE, previous studies suggested that it might be related to the disorder of cerebral blood flow, the destruction of blood-brain barrier and the injury of brain parenchyma cells caused by inflammatory factors. In recent years, studies have confirmed that the imbalance of REDOX homeostasis is also involved in the pathogenesis of HACE, which mainly leads to abnormal activation of microglia and destruction of tight junction of vascular endothelial cells through the excessive production of mitochondrial-related reactive oxygen species. Therefore, this review summarizes the role of REDOX homeostasis and the potential of the treatment of REDOX homeostasis in HACE, which is of great significance to expand the understanding of the pathogenesis of HACE. Moreover, it will also be helpful to further study the possible therapy of HACE related to the key link of REDOX homeostasis.
10.2147/JIR.S415695
Hyperbaric oxygen preconditioning for prevention of acute high-altitude diseases: Fact or fiction?
Frontiers in physiology
Acute high-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), have been recognized as potentially lethal diseases for altitude climbers. Various preconditioning stimuli, including hyperbaric oxygen (HBO), have been proposed to prevent acute high-altitude diseases. Herein, we reviewed whether and how HBO preconditioning could affect high-altitude diseases and summarized the results of current trials. Evidence suggests that HBO preconditioning may be a safe and effective preventive method for acute high-altitude diseases. The proposed mechanisms of HBO preconditioning in preventing high-altitude diseases may involve: 1) protection of the blood-brain barrier and prevention of brain edema, 2) inhibition of the inflammatory responses, 3) induction of the hypoxia-inducible factor and its target genes, and 4) increase in antioxidant activity. However, the optimal protocol of HBO preconditioning needs further exploration. Translating the beneficial effects of HBO preconditioning into current practice requires the "conditioning strategies" approach. More large-scale and high-quality randomized controlled studies are needed in the future.
10.3389/fphys.2023.1019103
Hiccups and Slurring of Speech: Atypical Presentation of High-Altitude Cerebral Edema.
Cureus
High-altitude cerebral edema (HACE) is one of the rare and severe form of high-altitude mountain sickness. Usually it presents as headache, altered mental status, ataxia in un-acclimatized person with rapid ascent to high altitude. Here we report a case of a 62-year-old male patient who had history of rapid ascent to high altitude and presented to the department of emergency after descent from high altitude with an atypical presentation as hiccups and slurring of speech. Magnetic resonance imaging (MRI) of brain showed white matter edema suggestive of HACE. The patient improved after treatment with supplemental oxygen, dexamethasone, and acetazolamide. He was discharged after three days of hospital stay with complete resolution of symptoms.
10.7759/cureus.34997
Serum vascular endothelial growth factor is a potential biomarker for acute mountain sickness.
Frontiers in physiology
Acute mountain sickness (AMS) is the most common disease caused by hypobaric hypoxia (HH) in high-altitude (HA) associated with high mortality when progressing to high-altitude pulmonary edema (HAPE) and/or high-altitude cerebral edema (HACE). There is evidence for a role of pro- and anti-inflammatory cytokines in development of AMS, but biological pathways and molecular mechanisms underlying AMS remain elusive. We aimed to measure changes in blood cytokine levels and their possible association with the development of AMS. 15 healthy mountaineers were included into this prospective clinical trial. All participants underwent baseline normoxic testing with venous EDTA blood sampling at the Bangor University in United Kingdom (69 m). The participants started from Beni at an altitude of 869 m and trekked same routes in four groups the Dhaulagiri circuit in the Nepali Himalaya. Trekking a 14-day route, the mountaineers reached the final HA of 5,050 m at the Hidden Valley Base Camp (HVBC). Venous EDTA blood sampling was performed after active ascent to HA the following morning after arrival at 5,050 m (HVBC). A panel of 21 cytokines, chemokines and growth factors were assessed using Luminex system (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-1ra, sIL-2Rα, IFN-γ, TNF-α, MCP-1, MIP-1α, MIP-1β, IP-10, G-CSF, GM-CSF, EGF, FGF-2, VEGF, and TGF-β1). There was a significant main effect for the gradual ascent from sea-level (SL) to HA on nearly all cytokines. Serum levels for TNF-α, sIL-2Rα, G-CSF, VEGF, EGF, TGF-β1, IL-8, MCP-1, MIP-1β, and IP-10 were significantly increased at HA compared to SL, whereas levels for IFN-γ and MIP-1α were significantly decreased. Serum VEGF was higher in AMS susceptible AMS resistant subjects ( < 0.027, main effect of AMS) and increased after ascent to HA in both AMS groups ( < 0.011, main effect of HA). Serum VEGF increased more from SL values in the AMS susceptible group than in the AMS resistant group ( < 0.049, interaction effect). Cytokine concentrations are significantly altered in HA. Within short interval after ascent, cytokine concentrations in HH normalize to values at SL. VEGF is significantly increased in mountaineers suffering from AMS, indicating its potential role as a biomarker for AMS.
10.3389/fphys.2023.1083808
Expression profile of cytokines and chemokines in a mouse high-altitude cerebral edema model.
International journal of immunopathology and pharmacology
INTRODUCTION:High-altitude cerebral edema (HACE) is considered to be the end-stage of acute mountain sickness (AMS); however, its pathophysiological mechanism remains unknown. Increasing evidences support that inflammation is an important risk factor for the occurrence of HACE. Including our published papers, previous studies demonstrated that the levels of IL-6, IL-1β, and TNF-α in both serum and hippocampus were increased in the mouse HACE model induced by LPS stimulation combined with hypobaric hypoxia exposure; however, the expression profile of other cytokines and chemokines remains unknown. OBJECTIVE:This study was to analyze the expression profile of cytokines and chemokines in the HACE model. METHODS:The mouse HACE model was established by LPS stimulation combined with hypobaric hypoxia exposure (LH). The mice were divided into the normoxic group, LH-6 h group, LH-1 d group, and LH-7 d group. Brain water content (BWC) was determined using the wet/dry weight ratio. The levels of 30 cytokines and chemokines in the serum and hippocampal tissue were detected using LiquiChip. The mRNA expression of cytokines and chemokines in hippocampal tissue were determined by -PCR. RESULTS:In the current study, we found that the brain water content was increased after the combinational treatment of LPS and hypobaric hypoxia. The results of LiquiChip showed that, in the serum and hippocampal tissue, most factors in all 30 cytokines and chemokines were dramatically upregulated at 6 h, and then declined at the 1st d and 7th d. Among these factors, G-CSF, M-CSF, MCP-1, KC, MIG, Eotaxin, Rantes, IP10, IL-6, MIP-2, and MIP-1β were all increased in both serum and hippocampal tissue at 6 h. In addition, the results of -PCR showed the mRNA levels of G-CSF, MCP-1, KC, MIG, Eotaxin, Rantes, IP10, IL-6, MIP-2, and MIP-1β in hippocampal tissue were dramatically upregulated at 6 h. CONCLUSION:This study showed that the dynamic expression profile of 30 cytokines and chemokines in a mouse HACE model induced by LPS plus hypobaric hypoxia. The levels of G-CSF, MCP-1, KC, MIG, Eotaxin, Rantes, IP10, IL-6, MIP-2, and MIP-1β in both serum and hippocampus were significantly increased at 6 h, which may be involved in the occurrence and development of HACE.
10.1177/03946320231177189
Structure and Function of the Blood-Brain Barrier (BBB).
Handbook of experimental pharmacology
The blood-brain barrier (BBB) protects the vertebrate central nervous system from harmful blood-borne, endogenous and exogenous substances to ensure proper neuronal function. The BBB describes a function that is established by endothelial cells of CNS vessels in conjunction with pericytes, astrocytes, neurons and microglia, together forming the neurovascular unit (NVU). Endothelial barrier function is crucially induced and maintained by the Wnt/β-catenin pathway and requires intact NVU for proper functionality. The BBB and the NVU are characterized by a specialized assortment of molecular specializations, providing the basis for tightening, transport and immune response functionality.The present chapter introduces state-of-the-art knowledge of BBB structure and function and highlights current research topics, aiming to understanding in more depth the cellular and molecular interactions at the NVU, determining functionality of the BBB in health and disease, and providing novel potential targets for therapeutic BBB modulation. Moreover, we highlight recent advances in understanding BBB and NVU heterogeneity within the CNS as well as their contribution to CNS physiology, such as neurovascular coupling, and pathophysiology, is discussed. Finally, we give an outlook onto new avenues of BBB research.
10.1007/164_2020_404
[High altitude illness and related diseases - a review].
Gudbjartsson Tomas,Sigurdsson Engilbert,Gottfredsson Magnus,Bjornsson Olafur Mar,Gudmundsson Gunnar
Laeknabladid
Upon reaching a height over 2500 m above seal level symptoms of altitude illness can develop over 1 - 5 days. The risk is mainly -determined by the altitude and rate of ascent and the symptoms vary. Most common are symptoms of acute mountain illness (AMS) but more dangerous high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE) can also develop. The causes of AMS, HACE and HAPE are lack of oxygen and insufficient acclimatization, but the presenting form is determined by the responses of the body to the lack of oxygen. The most common symptoms of AMS include headache, fatique and nausea, but insomnia and nausea are also common. The most common symptoms of HAPE are breathlessness and lassitude whereas the cardinal sign of HACE is ataxia, but confusion and loss of consciousness can also develop. In this article all three main forms of altitude illness are reviewed. The emphasis is on preventive measures and treatment but new knowledge on pathogenesis is also addressed.
10.17992/lbl.2019.11.257