Oxidative stress and expression of inflammatory factors in lung tissue of acute mountain sickness rats.

The aim of the present study was to investigate the changes in lung histomorphology and oxidative stress, as well as the expression of interleukin (IL)­17C and other inflammatory factors during acute mountain sickness (AMS) in male Sprague­Dawley rats and to explore the underlying mechanism. Rats were randomly divided into a control group (0 h) and three hypoxia stress groups, exposed to low­pressure oxygen storage at a simulated altitude of 6,000 m for 24, 48 and 72 h, respectively. Morphological changes in lung tissue were observed by hematoxylin and eosin staining under light microscopy and transmission electron microscopy. The expression of inflammatory factors IL­17C, nuclear factor­κB (NF­κB), IL­1ß, IL­6 and tumor necrosis factor­α (TNF­α) in lung tissue was assessed by RNA sequencing and verified by reverse transcription­quantitative PCR (RT­qPCR) and western blotting (WB). Superoxide dismutase (SOD) and glutathione peroxidase (GSH­Px) enzyme activity and malondialdehyde (MDA) expression were also measured. Experimental groups were compared to the control group following 24, 48 and 72 h of hypoxic stress. Lung tissue suffered from different degrees of injury, and the damage was the most severe after 48 h of hypoxic stress. RNA sequencing data from the lung tissue of rats from each group suggested that the expression of IL­17C, NF­κB, IL­1ß, IL­6, and TNF­α increased significantly after hypoxic stress. RT­qPCR and WB demonstrated that the expression of IL­17C and NF­κB increased significantly after hypoxia lasting 48 and 72 h. IL­1ß expression increased significantly after hypoxia stress lasting 24 and 48 h, and the expressions of TNF­α and IL­6 increased significantly after hypoxia stress lasting 24, 48 and 72 h (P<0.01). The enzyme activity of SOD and GSH­Px decreased significantly after lasting 24, 48 and 72 h of hypoxia (P<0.01), and MDA increased significantly after hypoxic stress lasting 48 and 72 h (P<0.01). In conclusion, under hypoxic stress, rats quickly initiate oxidative stress and immune responses. However, with prolonged hypoxic stress time, excessive oxidative stress can further stimulate the immune system in vivo, and release a large quantity of inflammatory factors accumulating in the body. This, in turn, may lead to the occurrence of inflammatory storms and further damage the lung tissue resulting in AMS.

High-altitude hypoxia exacerbates dextran sulfate sodium (DSS)-induced colitis by upregulating Th1 and Th17 lymphocytes.

High altitude hypoxia (HAH) involves the pathogenesis of ulcerative colitis (UC) and gastrointestinal erosions. However, the mechanism of effects of HAH in colitis remains controversial. This study reports the immunomodulation mediated by HAH to enhancing the severity of UC in the mice model. BALB/c mice were used to establish the UC model by dextran sulfate sodium (DSS) compared to wild type mice. Mice groups were exposed to hypoxic conditions in a hypobaric chamber with an altitude of 5000 m for 7 days. Then, Spleen, mesenteric lymph nodes and colon tissues were collected. The activity of UC, the infiltration of the immune cells, and the released cytokines were investigated. Results showed that the severity of DSS-induced UC significantly increased in mice exposed to HAH. The analysis of pathological changes showed increased weight loss and decreased colon length accompanied by diarrhea and bloody feces in the hypobaric hypoxia group. Interestingly, the levels of inflammatory cytokines IL-17, TNF-α, and IFN-γ in the spleen and mesenteric lymph node showed a significant increase within the colon of the hypobaric hypoxia group. The population of Th 1 and Th 17 cells in the spleen was significantly increased in mice exposed to hypobaric hypoxia compared NC group. Suggesting that high altitude hypoxia enhances colitis in mice through activating the increase of inflammatory Th1 and Th17 lymphocytes. In conclusion, this study revealed that hypobaric hypoxia directly increases the severity of UC in the mice model via increasing the activity of inflammatory CD4+ Th1 and Th 17 lymphocytes.

Research on the improvement of oxidative stress in rats with high-altitude pulmonary hypertension through the participation of irbesartan in regulating intestinal flora.

OBJECTIVE: High-altitude pulmonary hypertension (HAPH) is one of the diseases with higher occurrence among people living in plateau areas. The possible mechanism of angiotensin II receptor 1 inhibitor irbesartan in improving HAPH was explored from the perspective of intestinal bacterial flora in this study. MATERIALS AND METHODS: A HAPH rat model was established under simulated high-altitude hypobaric hypoxia. The levels of oxidative stress and vasoactive substances were detected after irbesartan intervention, and intestinal flora genomics analysis was performed. RESULTS: High-altitude hypobaric hypoxia-induced the increase in pulmonary artery pressure and left ventricular systolic dysfunction in HAPH model rats, but its effects were alleviated by irbesartan. Changes in the levels of oxidative damage in intestinal tissues, such as the increase in superoxide dismutase and glutathione peroxidase in intestinal tissues and the decrease in malondialdehyde content, were also reversed by irbesartan. The serum levels of angiotensin II, endothelin 1, interleukin-6, and C-reactive protein increased substantially whereas the level of nitric oxide decreased in HAPH model rats. The levels of these vasoconstriction and inflammatory indicators were also reversed after irbesartan intervention. The distribution of intestinal florae in rats was changed by the simulated high-altitude hypoxia environment as manifested by the increased Firmicutes-to-Bacteroidetes ratio (F/B), the increased abundance of Lactobacillaceae and Lachnospiraceae, and the decreased abundance of Prevotellaceae and Desulfovibrionaceae at the family level. However, the changes in F/B ratio and the abundance of these florae were reversed by irbesartan. CONCLUSIONS: Irbesartan can alleviate pulmonary artery pressure and left ventricular relaxation in HAPH model rats, reduce the oxidative damage caused by high-altitude hypoxia, and lower the release of vasoconstrictor factors and inflammatory mediators. These effects might be caused by the increased abundance of Lactobacillaceae and Lachnospiraceae and the decreased abundance of Prevotellaceae and Desulfovibrionaceae in the intestines.

Effects of Acute Exposure to Hypobaric Hypoxia on Mucosal Barrier Injury and the Gastrointestinal Immune Axis in Rats.

High altitude-induced gastrointestinal (GI) problems are potentially life-threatening. GI tract bleeding and inflammation are the major problems induced by hypobaric hypoxia (HH). In this study, effects of acute exposure to HH up to 14 days at 7620 m on GI immune function have been studied. To fulfill these objectives, Sprague-Dawley (SD) rats were divided into five groups namely Control and HH exposed (1, 3, 7, and 14 days). All groups except control were exposed to 7620 m of HH in an animal decompression chamber for the respective time intervals. Different degrees of intestinal mucosal damage in terms of increased mucosal permeability and disruption of intestinal villi were observed for different time intervals. HH exposure also upregulated secretory immunoglobulin A (sIgA) and proinflammatory cytokines in GI lavage along with proinflammatory markers such as toll-like receptor 4 (TLR4) and inducible nitric oxide synthase (iNOS). HH exposure of rats for 7 days significantly increased interleukin-17 (IL-17) and natural killer (NK) cell and dendritic cell populations compared with unexposed control rats. However, the number of naive T cells was significantly decreased in Peyer's patches. Our results connect HH to GI immune axis and highlight Th17 cells and proinflammatory molecules as potential therapeutic targets to counteract HH-induced GI dysfunction.

Performance and altitude: Ways that nutrition can help.

High altitudes are a challenge for human physiology and for sports enthusiasts. Several reasons lead to deterioration in performance at high altitudes. Hypoxia owing to high altitude causes a breakdown of homeostasis with imbalance in several physiological systems, including the immune system. The reduction in mucosal immunity and inflammation and the predominance of the humoral immune response causes a condition of immunosuppression and an increased likelihood of infection. In addition, it is known that worsening of the immune response is associated with reduced performance. On the other hand, immunonutrition plays an important role in modulating the effects of physical exercise on the immune system. However, to our knowledge, few studies have evaluated the effect of nutrition on the immune system after exercise in hypoxia. Although the association between exercise and hypoxia has been shown to be more severe for the body owing to the sum of stressful agents, supplementation with carbohydrates and glutamine seems to play a relevant role in mitigating immunosuppressive effects. These findings, although limited by the fact that they are the result of very few studies, shed light on a relevant theme for sports physiology and nutrition and suggest that both supplements may be useful for athletes, visitors, and workers in high-altitude regions. The aim of this review was to discuss the effects of high-altitude hypoxia on the human body from the point of view of exercise immunology because it is known that transient immunosuppression after strenuous exercise and competition should be followed by reduction in training overload and worse performance.

Vitamin E Reduces Hypobaric Hypoxia-Induced Immune Responses in Male Rats.

In hypobaric hypoxia (HH) at high altitude, the immune responses are changed probably due to oxidative stress-induced production of free radicals and nonradicals. Vitamin E is an antioxidant and protects the cells from oxidative damage. The present study was carried out to study the antioxidant role of vitamin E on the immune changes induced by oxidative stress in HH at high altitude. Select immune responses (phagocytic activity of white blood cell [WBC], cytotoxic activity of splenic mononuclear cells [MNCs], and delayed type of hypersensitivity [DTH]) and hematological changes (total count and differential count [DC] of WBC) were measured in male rats exposed to intermittent HH (at 5486.4 m in a simulated chamber for 8 hours/d for 6 consecutive days) and in normobaric condition with and without p.o. administration of vitamin E in three different doses (20, 40, and 60 mg/kg body weight). The increase of phagocytic activity of blood WBC, and reduction of cytotoxic activity of splenic MNC and DTH response were observed in rats exposed to HH. After the administration of vitamin E at different doses, the immune changes were blocked in a dose-dependent manner. Exposure to HH also led to the elevation of serum corticosterone (CORT), which was arrested after administration of vitamin E. The results indicate that the immune changes in HH at high altitude are probably mediated by the production of free radicals and nonradicals, and vitamin E can block these immune changes by its reactive oxygen species quenching effects.

WIP1 Phosphatase Plays a Critical Neuroprotective Role in Brain Injury Induced by High-Altitude Hypoxic Inflammation.

The hypobaric hypoxic environment in high-altitude areas often aggravates the severity of inflammation and induces brain injury as a consequence. However, the critical genes regulating this process remain largely unknown. The phosphatase wild-type p53-induced phosphatase 1 (WIP1) plays important roles in various physiological and pathological processes, including the regulation of inflammation in normoxia, but its functions in hypoxic inflammation-induced brain injury remain unclear. Here, we established a mouse model of this type of injury and found that WIP1 deficiency augmented the release of inflammatory cytokines in the peripheral circulation and brain tissue, increased the numbers of activated microglia/macrophages in the brain, aggravated cerebral histological lesions, and exacerbated the impairment of motor and cognitive abilities. Collectively, these results provide the first in vivo evidence that WIP1 is a critical neuroprotector against hypoxic inflammation-induced brain injury.

[Decreased number and immune activity of splenic T lymphocytes in mice exposed to hypoxia at high altitude].

Objective: To explore the changes of splenic T lymphocyte subsets and functions in mice under high-altitude hypoxic conditions. Methods: After mice were exposed to an altitude of 400 m,2200 m and 4200 m for 30 days,ELISA was used to detect the concentrations of interleukin-4( IL-4) and interferon-γ( IFN-γ) in the cultured splenocyte supernatant; MTT assay was used to analyze the proliferation of splenic T lymphocytes; flow cytometry was performed to examine the alterations of splenic T lymphocyte subsets. Results: After exposed to hypoxia for 30 days,in comparison with the control group( 400 m),the spleen index of the mice increased significantly in both the 2200 m and 4200 m groups,and the spleen index of the 4200 m group was apparently higher than that of the 2200 m group; the concentration of IFN-γ in the splenocyte supernatant of the 4200 m and 2200 m groups significantly decreased,while the concentration of IL-4 had no obvious change. The proliferation of splenic T lymphocyte was reduced obviously in both the 2200 m and 4200 m groups,at the same time,the proliferation of T cells in the 4200 m group was markedly lower than that in the 2200 m group. The percentages of splenic CD3~+,CD4~+and CD8~+T lymphocytes decreased markedly in the 2200 m and 4200 m groups,among them,the number of CD4~+T cel s decreased significantly than CD8~+T cel s. In addition,CD3~+and CD4~+T lymphocyte percentages of the 4200 m group obviously decreased compared with the 2200 m group. Conclusion: In mice exposed to hypoxia at an altitude of 4200 m and 2200 m for 30 days,the number of T lymphocyte subsets and the proliferation ability of T cel s decrease,and the level of IFN-γ is decreased as well.

Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema.

Introduction. Acute exposure to high altitude induces inflammation. However, the relationship between inflammation and high altitude related illness such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) is poorly understood. We tested if soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration, a prognostic factor for cardiovascular disease and marker for low grade activation of leukocytes, will predict susceptibility to HAPE and AMS. Methods. 41 healthy mountaineers were examined at sea level (SL, 446 m) and 24 h after rapid ascent to 4559 m (HA). 24/41 subjects had a history of HAPE and were thus considered HAPE-susceptible (HAPE-s). Out of the latter, 10/24 HAPE-s subjects were randomly chosen to suppress the inflammatory cascade with dexamethasone 8 mg bid 24 h prior to ascent. Results. Acute hypoxic exposure led to an acute inflammatory reaction represented by an increase in suPAR (1.9 ± 0.4 at SL versus 2.3 ± 0.5 at HA, p < 0.01), CRP (0.7 ± 0.5 at SL versus 3.6 ± 4.6 at HA, p < 0.01), and IL-6 (0.8 ± 0.4 at SL versus 3.3 ± 4.9 at HA, p < 0.01) in all subjects except those receiving dexamethasone. The ascent associated decrease in PaO2 correlated with the increase in IL-6 (r = 0.46, p < 0.001), but not suPAR (r = 0.27, p = 0.08); the increase in IL-6 was not correlated with suPAR (r = 0.16, p = 0.24). Baseline suPAR plasma concentration was higher in the HAPE-s group (2.0 ± 0.4 versus 1.8 ± 0.4, p = 0.04); no difference was found for CRP and IL-6 and for subjects developing AMS. Conclusion. High altitude exposure leads to an increase in suPAR plasma concentration, with the missing correlation between suPAR and IL-6 suggesting a cytokine independent, leukocyte mediated mechanism of low grade inflammation. The correlation between IL-6 and PaO2 suggests a direct effect of hypoxia, which is not the case for suPAR. However, suPAR plasma concentration measured before hypoxic exposure may predict HAPE susceptibility.

Effect of acute exercise and hypoxia on markers of systemic and mucosal immunity.

PURPOSE: To determine how immune markers are affected by acute hypoxic exercise at the same relative intensity. METHODS: Twelve endurance-trained males (age: 28 ± 4 years, [Formula: see text]O2max: 63.7 ± 5.3 mL/kg/min) cycled for 75 min at 70 % of altitude-specific [Formula: see text]O2max, once in normoxia (N) and once in hypobaric hypoxia equivalent to 2000 m above sea-level (H). Blood and saliva samples were collected pre-, post- and 2 h post-exercise. RESULTS: Participants cycled at 10.5 % lower power output in H vs. N, with no significant differences in heart rate (P = 0.10) or rating of perceived exertion (P = 0.21). Post-exercise plasma cortisol was higher in H vs. N [683 (95 % CI 576-810) nmol/l vs. 549 (469-643) nmol/l, P = 0.017]. The exercise-induced decrease in CD4:CD8 ratio was greater in H vs. N (-0.5 ± 0.2 vs. -0.3 ± 0.2, P = 0.019). There were no significant between-trial differences for adrenocorticotropic hormone, plasma cytokines, antigen-stimulated cytokine production, salivary immunoglobulin-A or lactoferrin. However, there was a main trial effect for concentration [F(11) = 5.99, P < 0.032] and secretion [F(11) = 5.01, P < 0.047] of salivary lysozyme, with this being higher in N at every time-point. CONCLUSION: Whether the observed differences between H and N are of sufficient magnitude to clinically impair host defence is questionable, particularly as they are transient in nature and since other immune markers are unaffected. As such, acute hypoxic exercise likely does not pose a meaningful additional threat to immune function compared to exercise at sea level, provided that absolute workload is reduced in hypoxia so that relative exercise intensity is the same.

Low ambient oxygen prevents atherosclerosis.

Large population studies have shown that living at higher altitudes, which lowers ambient oxygen exposure, is associated with reduced cardiovascular disease mortality. However, hypoxia has also been reported to promote atherosclerosis by worsening lipid metabolism and inflammation. We sought to address these disparate reports by reducing the ambient oxygen exposure of ApoE-/- mice. We observed that long-term adaptation to 10% O2 (equivalent to oxygen content at ∼5000 m), compared to 21% O2 (room air at sea level), resulted in a marked decrease in aortic atherosclerosis in ApoE-/- mice. This effect was associated with increased expression of the anti-inflammatory cytokine interleukin-10 (IL-10), known to be anti-atherogenic and regulated by hypoxia-inducible transcription factor-1α (HIF-1α). Supporting these observations, ApoE-/- mice that were deficient in IL-10 (IL10-/- ApoE-/- double knockout) failed to show reduced atherosclerosis in 10% oxygen. Our study reveals a specific mechanism that can help explain the decreased prevalence of ischemic heart disease in populations living at high altitudes and identifies ambient oxygen exposure as a potential factor that could be modulated to alter pathogenesis. Key messages: Chronic low ambient oxygen exposure decreases atherosclerosis in mice. Anti-inflammatory cytokine IL-10 levels are increased by low ambient O2. This is consistent with the established role of HIF-1α in IL10 transactivation. Absence of IL-10 results in the loss of the anti-atherosclerosis effect of low O2. This mechanism may contribute to decreased atherosclerosis at high altitudes.

Effects of vitamin C on the hypobaric hypoxia-induced immune changes in male rats.

Hypobaric hypoxia (HH) induces oxidative stress (OS) and is associated with the generation of reactive oxygen species (ROS). Vitamin C is an efficient antioxidant, and it is used in a high-altitude environment to reduce the OS. The present study explores the role of vitamin C on some HH-induced changes of immune parameters in rats which were exposed to HHc condition at 18,000 ft in a simulated chamber for 8 h/day for 6 days with and without vitamin C administration at three different doses (200, 400, and 600 mg/kg body wt). The phagocytic activity of circulating blood WBC was increased, and the cytotoxic activity of splenic mononuclear cell (MNC) and the delayed type of hypersensitivity (DTH) responses to bovine serum albumin (BSA) were decreased in rats exposed to HHc condition, but these immune changes were blocked after administration of vitamin C at 400 mg/kg body wt. The leukocyte adhesive inhibition index (LAI) was not altered either in HHc condition or after administration of vitamin C in HHc condition. The serum corticosterone (CORT) concentration was increased in rats exposed to HHc condition which was blocked after administration of vitamin C (400 mg/kg body wt). The immune parameters and serum CORT concentration, however, did not show any recovery after administration of vitamin C at the dose of 200 and 600 mg/kg body wt. The present study indicates that administration of vitamin C at a dose of 400 mg/kg body wt may prevent the HH-induced immunological changes but not at the lower dose (200 mg/kg body wt) or higher dose (600 mg/kg body wt) in rats.

Influence of high altitude exposure on the immune system: a review.

High altitude may be defined as elevations as low as 1500 meters to those as high as 8800 meters. Very few studies have been conducted so far at high altitude for the specific purpose of monitoring different immune parameters in humans. Military personnel and mountaineers may be required to perform in environmental extremes such as high altitude. The stressors they experience are numerous and varied, e.g., high altitude, humidity and the availability of food and water, prolonged moderate to heavy physical activities, limited or inadequate sleep, increased susceptibility to infection and injury, etc. In this article we review the immunological consequences of high altitude exposure.

Relationship between stress hormones and immune response during high-altitude exposure in women.

We previously confirmed that high altitude (HA) exposure can modify the number and function of immune cells, leading to a disruption in the homeostatic regulation of T helper1 (Th1)/T helper2 (Th2) immune responses. Our aim was to evaluate possible relationships between the stress response and immunological parameters during HA exposure. Thirteen healthy women spent 21 days at 5050 m. Before (SL1), the first and the 21st day at HA (HA1 and HA2, respectively), and the day after returning at sea level (SL2), we collected blood samples for immunologic parameters, and 24-h urine samples for norepinephrine, epinephrine, and cortisol. Norepinephrine and cortisol significantly increased (p<0.01) at HA1 and HA2 compared to SL1, while epinephrine did not change. At HA1, CD3+ T-cell fell significantly (p<0.001) with respect to SL1, owing to a significant (p<0.001) CD4+ T-cell reduction, while CD16+ and CD56+ increased (p<0.001) at HA2 compared to SL1. The expression of interferon-gamma (IFN-gamma) decreased (p<0.0005) at HA1 and HA2 with respect to SL1. At HA1 different lymphocyte subset (CD3+, CD4+, CD19+) were well correlated with epinephrine (p<0.05), whereas in analyzing the combined data (SL1-HA1-HA2-SL2), CD3+ (r=-0.310), CD4+ (r=-0.332), CD16+ (r=0.404), and CD56+ (r=0.373) demonstrated moderate but significant correlations (p<0.05) with norepinephrine. Moreover, norepinephrine levels were inversely correlated (r=-0.591; p<0.001) with IFN-gamma expression, a typical Th1 cytokine. We suggest that the sympatho-adrenal axis may have a role on the immunologic adaptations observed during HA exposure, and specifically on the observed impairment of the Th1/Th2 immune balance.

Leukocyte counts and neutrophil activity during 4 h of hypocapnic hypoxia equivalent to 4000 m.

INTRODUCTION: Symptoms and signs of infectious disease are increased in subjects at altitude. Most infections at altitude are diagnosed clinically and do not have objective data to support the diagnosis. Since in vivo innate immune responses to hypoxia have not been thoroughly characterized, we investigated the effect of acute systemic hypocapnic hypoxia on leukocyte trafficking and neutrophil activity in healthy humans at rest. METHODS: Sixteen male subjects [mean +/- SD age 28.3 +/- 6.5 yrs, body mass 80.9 +/- 15.9 kg, Vo2peak 4.10 +/- 0.76 L x min(-1)] breathed a hypoxic gas mixture (F(IO)2 = 12.2%, equivalent to 4000 m; H) or normoxic room air (F(IO)2 = 20.9%; N) for 240 min, via a mouthpiece, followed by 60 min of normal breathing. RESULTS: H induced a differential response in peripheral venous blood neutrophils (p < 0.05), lymphocytes (p < 0.01), and eosinophils (p < 0.01; 60-240 min), resulting in a relative lymphopenia (H 1.88 +/- 0.48 and N 2.14 +/- 0.45 x 10(9) L(-1)) and neutrophilia (H 5.2 +/- 1.8 and N 3.9 +/- 1.1 x 10(9) L(-1)) by 240 and 300 min, respectively. Unstimulated leukocyte oxidative activity, as determined by luminol enhanced chemiluminescence; plasma elastase, a marker of in vivo neutrophil degranulation; and sP-selectin, a marker of endothelial cell activation, did not change throughout. DISCUSSION: Differences in immune cell numbers showed a marked similarity to changes previously reported in response to intense short- and long-duration exercise and were attributed to the physiological responses induced by acute hypoxia that are known to mediate immune cell trafficking. These findings could be relevant to the etiology of conditions where hypoxia and immune cells are implicated.

Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor.

CONTEXT: The pathogenesis of high-altitude pulmonary edema (HAPE) is considered an altered permeability of the alveolar-capillary barrier secondary to intense pulmonary vasoconstriction and high capillary pressure, but previous bronchoalveolar lavage (BAL) findings in well-established HAPE are also consistent with inflammatory etiologic characteristics. OBJECTIVES: To determine whether inflammation is a primary event in HAPE and to define the temporal sequence of events in HAPE. DESIGN, SETTING, AND PARTICIPANTS: Case study from July through August 1999 of 10 subjects with susceptibility to HAPE and 6 subjects resistant to HAPE, all of whom are nonprofessional alpinists with previous mountaineering experience above 3000 m. MAIN OUTCOME MEASURES: Pulmonary artery pressure measurements and BAL findings at low altitude (490 m) and shortly before or at the onset of HAPE at an altitude of 4559 m. RESULTS: Subjects who were HAPE susceptible had higher mean (SD) pulmonary artery systolic blood pressures at 4559 m compared with HAPE-resistant subjects (66 vs 37 mm Hg; P =.004). Despite development of HAPE in the majority of HAPE-susceptible subjects, there were no differences in BAL fluid total leukocyte counts between resistant and susceptible subjects or between counts taken at low and high altitudes. Subjects who developed HAPE had BAL fluid with high concentrations of plasma-derived proteins and erythrocytes, but there was no increase in plasma concentrations of surfactant protein A and Clara cell protein. The chest radiograph score was 12.7 for the 3 HAPE-susceptible subjects who developed HAPE before BAL was performed; they were lavaged within 3 to 5 hours. The remainder of the HAPE-susceptible group was lavaged before edema was apparent on radiographs. However, 6 subjects from the HAPE-susceptible group who developed HAPE on the following day had a score on bronchoscopy of 1.5, which increased to 4.6, reflective of mild pulmonary edema. In HAPE cases, there were no elevations in a number of proinflammatory cytokines and eicosanoid and nitric oxide metabolites. CONCLUSIONS: Early HAPE is characterized by high pulmonary artery pressures that lead to a protein-rich and mildly hemorrhagic edema, with normal levels of leukocytes, cytokines, and eicosanoids. HAPE is a form of hydrostatic pulmonary edema with altered alveolar-capillary permeability.

Upregulation of adrenocorticotrophic hormone in the corticotrophs and downregulation of surface receptors and antigens on the macrophages in the adenohypophysis following an exposure to high altitude.

Altitude exposures lead to the development of hypobaric hypoxia because of low oxygen tension in the ambient air. This study has shown the vigorous upregulation of adrenocorticotrophic hormone (ACTH) expression in corticotrophs of the pars distalis (adenohypophysis) of rats 1-7 days after an altitude exposure. Concomitant to this was the increase in number and hypertrophy of the immunoreactive corticotrophs. It was suggested that this had resulted in an upsurge of ACTH production which may have suppressed the immuno-expression of complement type 3 receptors and major histocompatibility complex class II antigens constitutively expressed by the parenchymal macrophages through paracrine action. Along with ACTH, altered levels of other hormones following such exposures may also contribute to suppression of antigen presenting function and phagocytic activity of macrophages. The effects of altitude (hypobaric hypoxia) exposure, however, were reversible as the above immunohistochemical changes returned to normal 21-28 days after the hypobaric hypoxic insult.

Update: High altitude pulmonary edema.

Recent high altitude studies with pulmonary artery (PA) catheterization and broncho-alveolar lavage (BAL) in early high altitude pulmonary edema(HAPE) have increased our understanding of the pathogenetic sequence in HAPE. High preceding PA and pulmonary capillary pressures lead to a non-inflammatory leak of the alveolar-capillary barrier with egress of red cells, plasma proteins and fluid into the alveolar space. The mechanisms accounting for an increased capillary pressure remain speculative. The concept that hypoxic pulmonary vasoconstriction (HPV) is uneven so that regions with less vasoconstriction are over-perfused and become edematous remains compelling but unproved. Also uncertain is the role and extent of pulmonary venoconstriction. With disruption of the normal alveolar-capillary barrier, some individuals may later develop a secondary inflammatory reaction. A high incidence of preceding or concurrent respiratory infection in children with HAPE has been used to support a causative role of inflammation in HAPE. However, alternatively even mild HPV may simply lower the threshold at which inflammation-mediated increases in alveolar capillary permeability cause significant fluid flux into the lung. Other major questions to be addressed in future research are: 1.) What is the mechanism of exaggerated hypoxic pulmonary vasoconstriction? Is there a link to primary pulmonary hypertension? Several observations suggest that susceptibility to HAPE is associated with endothelial dysfunction in pulmonary vessels. This has not yet been studied adequately. 2.) What is the nature of the leak? Is there structural damage, i. e. stress failure, or does stretch cause opening of pores? 3.) What is the pathophysiologic significance of a decreased sodium and water clearance across alveolar epithelial cells in hypoxia? 4.) What is the role of exercise? Do HAPE-susceptible individuals develop pulmonary edema when exposed to hypoxia without exercise? Answers to these questions will increase our understanding of the pathophysiology of HAPE and also better focus research on the genetic basis of susceptibility to HAPE.

Association of high-altitude pulmonary edema with the major histocompatibility complex.

BACKGROUND: A constitutional susceptibility has been suggested in the development of high-altitude pulmonary edema (HAPE) because HAPE generally affects healthy young people, some of whom suffer recurrent episodes. We examined whether immunogenetic susceptibility is present in HAPE-susceptible subjects. METHODS AND RESULTS: The frequencies of human leukocyte antigen (HLA) alleles in 28 male and 2 female subjects with a history of HAPE were compared with those in 100 healthy volunteers. We assayed the HLA-A, -B, -C, -DR, and -DQ antigens serologically. The pulmonary hemodynamics on admission to the hospital and the ventilatory response to hypoxia and hypercapnia were retrospectively examined in 10 of the HAPE-susceptible subjects. HLA-DR6 was positive in 14 (46.7%) of the subjects with HAPE but only 16.0% of the control subjects (P=.0005), and HLA-DQ4 was positive in 12 (40.0%) of the subjects with HAPE but only 10.0% of the control subjects (P=.0001). HLA-DR6 or HLA-DQ4 was positive in 8 (100%) of the subjects with recurrent HAPE. The pulmonary arterial pressure on admission of the HLA-DR6-positive subjects with HAPE was significantly higher than that of the HLA-DR6-negative subjects with HAPE. CONCLUSIONS: There were significant associations of HAPE with HLA-DR6 and HLA-DQ4 and of pulmonary hypertension with HLA-DR6. An immunogenetic susceptibility, which is associated with HLA class II alleles located within the major histocompatibility complex, may underlie the development of HAPE, at least in some of its forms.