Contact phase of blood coagulation is not activated in edema of high altitude

To examine whether bradykinin generated by the activation of the contact phase of blood coagulation is involved in the pathogenesis of edema occurring after acute exposure to high altitude, 15 mountaineers were examined at 490 m and 1, 3, and 5 days after arrival at 4,559 m. The clotting activity levels of factor XII, factor XI, plasma prekallikrein, and high-molecular-weight kininogen (HMWK) were measured, and plasma kallikrein-induced proteolytic cleavage of HMWK was assessed by ligand blotting by use of radiolabeled factor XI. After an ascent on foot from 1,170 to 4,559 m in 3 days, three subjects developed high-altitude pulmonary edema, and four subjects presented facial edema. There was no evidence for activation of the contact system in any subject as demonstrated by the lack of proteolytic cleavage of HMWK at high altitude. The absence of contact system activation was further supported by stable plasma levels of the individual factors of contact activation. Therefore, we conclude that bradykinin generated by plasma kallikrein-induced cleavage of HMWK is not involved in the pathogenesis of edema due to acute exposure to high altitude.     

Blood rheology in acute mountain sickness and high-altitude pulmonary edema.

The role of blood rheology in the pathogenesis of acute mountain sickness and high-altitude pulmonary edema was investigated. Twenty-three volunteers, 12 with a history of high-altitude pulmonary edema, were studied at low altitude (490 m) and at 2 h and 18 h after arrival at 4,559 m. Eight subjects remained healthy, seven developed acute mountain sickness, and eight developed high-altitude pulmonary edema. Hematocrit, whole blood viscosity, plasma viscosity, erythrocyte aggregation, and erythrocyte deformability (filtration) were measured. Plasma viscosity and erythrocyte deformability remained unaffected. The hematocrit level was lower 2 h after the arrival at high altitude and higher after 18 h compared with low altitude. The whole blood viscosity changed accordingly. The erythrocyte aggregation was about doubled 18 h after the arrival compared with low-altitude values, which reflects the acute phase reaction. There were, however, no significant differences in any rheological parameters between healthy individuals and subjects with acute mountain sickness or high-altitude pulmonary edema, either before or during the illness. We conclude that rheological abnormalities can be excluded as an initiating event in the development of acute mountain sickness and high-altitude pulmonary edema.     

Pulmonary artery pressure and cardiac function in children and adolescents after rapid ascent to 3,450 m

High-altitude destinations are visited by increasing numbers of children and adolescents. High-altitude hypoxia triggers pulmonary hypertension that in turn may have adverse effects on cardiac function and may induce life-threatening high-altitude pulmonary edema (HAPE), but there are limited data in this young population. We, therefore, assessed in 118 nonacclimatized healthy children and adolescents (mean ± SD; age: 11 ± 2 yr) the effects of rapid ascent to high altitude on pulmonary artery pressure and right and left ventricular function by echocardiography. Pulmonary artery pressure was estimated by measuring the systolic right ventricular to right atrial pressure gradient. The echocardiography was performed at low altitude and 40 h after rapid ascent to 3,450 m. Pulmonary artery pressure was more than twofold higher at high than at low altitude (35 ± 11 vs. 16 ± 3 mmHg; P < 0.0001), and there existed a wide variability of pulmonary artery pressure at high altitude with an estimated upper 95% limit of 52 mmHg. Moreover, pulmonary artery pressure and its altitude-induced increase were inversely related to age, resulting in an almost twofold larger increase in the 6- to 9- than in the 14- to 16-yr-old participants (24 ± 12 vs. 13 ± 8 mmHg; P = 0.004). Even in children with the most severe altitude-induced pulmonary hypertension, right ventricular systolic function did not decrease, but increased, and none of the children developed HAPE. HAPE appears to be a rare event in this young population after rapid ascent to this altitude at which major tourist destinations are located.     

Serial changes in nasal potential difference and lung electrical impedance tomography at high altitude.

Recent work suggests that treatment with inhaled beta(2)-agonists reduces the incidence of high-altitude pulmonary edema in susceptible subjects by increasing respiratory epithelial sodium transport. We estimated respiratory epithelial ion transport by transepithelial nasal potential difference (NPD) measurements in 20 normal male subjects before, during, and after a stay at 3,800 m. NPD hyperpolarized on ascent to 3,800 m (P < 0.05), but the change in potential difference with superperfusion of amiloride or isoprenaline was unaffected. Vital capacity (VC) fell on ascent to 3,800 m (P < 0.05), as did the normalized change in electrical impedance (NCI) measured over the right lung parenchyma (P < 0.05) suggestive of an increase in extravascular lung water. Echo-Doppler-estimated pulmonary artery pressure increases were insufficient to cause clinical pulmonary edema. There was a positive correlation between VC and NCI (R(2) = 0.633) and between NPD and both VC and NCI (R(2) = 0.267 and 0.418). These changes suggest that altered respiratory epithelial ion transport might play a role in the development of subclinical pulmonary edema at high altitude in normal subjects.     

Physicians on Mount Everest—A Clinical Account of the 1981 American Medical Research Expedition to Everest

The American Medical Research Expedition to Everest had a wide variety of medical problems, ranging from leech bites to high-altitude pulmonary edema. Preventive measures, however, such as careful attention to ingesting only pure water and food at the lower elevations and adequate personal hydration, nutrition and rest at extremely high altitude minimized the morbidity suffered by the group. Prophylactic administration of doxycycline was effective in reducing the severity of diarrheal illness in the group. Every member of the expedition suffered upper respiratory tract infections and many other infections, some of which were resistant to all therapy until the patient moved down from high altitude. Despite careful acclimatization, several cases of acute mountain sickness occurred and required descent to a lower altitude for treatment. Frostbite was avoided entirely.     

Serum erythropoietin in humans at high altitude and its relation to plasma renin

Serum immunoreactive erythropoietin (siEp) was estimated in samples collected from members of two scientific and mountaineering expeditions, to Mount Kongur in Western China and to Mount Everest in Nepal. SiEp was increased above sea-level control values 1 and 2 days after arrival at 3,500 m and remained high on ascent to 4,500 m. Thereafter, while subjects remained at or above 4,500 m, siEp declined, and by 22 days after the ascent to 4,500 m was at control values but increased on ascent to higher altitude. Thus siEp was at a normal level during the maintenance of secondary polycythemia from high-altitude exposure. On descent, with removal of altitude hypoxia, siEp decreased, but despite secondary polycythemia levels remained measurable and in the range found in subjects normally resident at sea level. On Mount Everest, siEp was significantly (P less than 0.01) elevated above preexpedition sea-level controls after 2-4 wk at or above 6,300 m. There was no correlation between estimates of siEp and plasma renin activity in samples collected before and during both expeditions.     

急性高原病的预防性用药

急性高原病是暴露于高原时,因高原低氧而在数小时至数天内出现的临床症候群,若不及时诊治,会发展为较为严重的高原肺水肿和高原脑水肿。随着我国对西部地区投入力度的增加,内地人员进入高原地区日渐增多,因此如何保证进入高原的人员健康,是医药科研工作的一项重要任务。为使人们有效快速地预防急性高原病,本文对国内外使用较为普遍的药物以及它们的作用机制进行了概述;并对有良好应用前景的药物进行了介绍。     

急性高原病的预防性用药

急性高原病是暴露于高原时,因高原低氧而在数小时至数天内出现的临床症候群,若不及时诊治,会发展为较为严重的高原肺水肿和高原脑水肿。随着我国对西部地区投入力度的增加,内地人员进入高原地区日渐增多,因此如何保证进入高原的人员健康,是医药科研工作的一项重要任务。为使人们有效快速地预防急性高原病,本文对国内外使用较为普遍的药物以及它们的作用机制进行了概述;并对有良好应用前景的药物进行了介绍。     

Operation Everest II: man at extreme altitude

Rapid ascent to high altitude may cause serious problems for climbers, skiers, and aviators. In contrast, gradual ascent enables humans to function where the unacclimatized cannot. To examine changes in the O2 transport system that produce acclimatization, eight men were taken in a decompression chamber (without other stresses experienced on high mountains) to a simulated altitude of 8,840 m (29,028 ft, ambient PO2 = 43 Torr) in 40 days. Maximal O2 uptake fell to 1.2 l/min, and arterial PO2 and PCO2 were 30 and 11 Torr, respectively, with arterial pH of 7.56. Many sophisticated studies were done: Swan-Ganz catheterization and inert gas diffusion studies at three altitudes showed that normal cardiac function persisted, pulmonary vascular resistance increased and at extreme altitude was not lowered by O2, and pulmonary ventilation-perfusion mismatch increased, though variably. This appears to be an important factor limiting performance at extreme altitude. This paper presents the background, general approach, and a summary of major observations reported in detail in other papers.     

Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness.

Vascular endothelial growth factor (VEGF) is a hypoxia-induced protein that produces vascular permeability, and limited evidence suggests a possible role for VEGF in the pathophysiology of acute mountain sickness (AMS) and/or high-altitude cerebral edema (HACE). Previous studies demonstrated that plasma VEGF alone does not correlate with AMS; however, soluble VEGF receptor (sFlt-1), not accounted for in previous studies, can bind VEGF in the circulation, reducing VEGF activity. In the present study, we hypothesized that free VEGF is greater and sFlt-1 less in subjects with AMS compared with well individuals at high altitude. Subjects were exposed to 4,300 m for 19-20 h (baseline 1,600 m). The incidence of AMS was determined by using a modified Lake Louise symptom score and the Environmental Symptoms Questionnaire for cerebral effects. Plasma was collected at low altitude and after 24 h at high altitude, or at time of illness, and then analyzed by ELISA for VEGF and for soluble VEGF receptor, sFlt-1. AMS subjects had lower sFlt-1 at both low and high altitude compared with well subjects and a significant rise in free plasma VEGF on ascent to altitude compared with well subjects. We conclude that increased free plasma VEGF on ascent to altitude is associated with AMS and may play a role in pathophysiology of AMS.     

Impact of acute hypoxic pulmonary hypertension on LV diastolic function in healthy mountaineers at high altitude

In pulmonary hypertension right ventricular pressure overload leads to abnormal left ventricular (LV) diastolic function. Acute high-altitude exposure is associated with hypoxia-induced elevation of pulmonary artery pressure particularly in the setting of high-altitude pulmonary edema. Tissue Doppler imaging (TDI) allows assessment of LV diastolic function by direct measurements of myocardial velocities independently of cardiac preload. We hypothesized that in healthy mountaineers, hypoxia-induced pulmonary artery hypertension at high altitude is quantitatively related to LV diastolic function as assessed by conventional and TDI Doppler methods. Forty-one healthy subjects (30 men and 11 women; mean age 41 +/- 12 yr) underwent transthoracic echocardiography at low altitude (550 m) and after a rapid ascent to high altitude (4,559 m). Measurements included the right ventricular to right atrial pressure gradient (DeltaP(RV-RA)), transmitral early (E) and late (A) diastolic flow velocities and mitral annular early (E(m)) and late (A(m)) diastolic velocities obtained by TDI at four locations: septal, inferior, lateral, and anterior. At a high altitude, DeltaP(RV-RA) increased from 16 +/- 7 to 44 +/- 15 mmHg (P < 0.0001), whereas the transmitral E-to-A ratio (E/A ratio) was significantly lower (1.11 +/- 0.27 vs. 1.41 +/- 0.35; P < 0.0001) due to a significant increase of A from 52 +/- 15 to 65 +/- 16 cm/s (P = 0.0001). DeltaP(RV-RA) and transmitral E/A ratio were inversely correlated (r(2) = 0.16; P = 0.0002) for the whole spectrum of measured values (low and high altitude). Diastolic mitral annular motion interrogation showed similar findings for spatially averaged (four locations) as well as for the inferior and septal locations: A(m) increased from low to high altitude (all P < 0.01); consequently, E(m)/A(m) ratio was lower at high versus low altitude (all P < 0.01). These intraindividual changes were reflected interindividually by an inverse correlation between DeltaP(RV-RA) and E(m)/A(m) (all P < 0.006) and a positive association between DeltaP(RV-RA) and A(m) (all P < 0.0009). In conclusion, high-altitude exposure led to a two- to threefold increase in pulmonary artery pressure in healthy mountaineers. This acute increase in pulmonary artery pressure led to a change in LV diastolic function that was directly correlated with the severity of pulmonary hypertension. However, in contrast to patients suffering from some form of cardiopulmonary disease and pulmonary hypertension, in these healthy subjects, overt LV diastolic dysfunction was not observed because it was prevented by augmented atrial contraction. We propose the new concept of compensated diastolic (dys)function.     

The physiology and biomechanics of avian flight at high altitude

Many birds fly at high altitude, either during long-distanceflights or by virtue of residence in high-elevation habitats.Among the many environmental features that vary systematicallywith altitude, five have significant consequences for avianflight performance: ambient wind speeds, air temperature, humidity,oxygen availability, and air density. During migratory flights,birds select flight altitudes that minimize energy expenditurevia selection of advantageous tail- and cross-winds. Oxygenpartial pressure decreases substantially to as little as 26%of sea-level values for the highest altitudes at which birdsmigrate, whereas many taxa reside above 3000 meters in hypoxicair. Birds exhibit numerous adaptations in pulmonary, cardiovascular,and muscular systems to alleviate such hypoxia. The systematicdecrease in air density with altitude can lead to a benefitfor forward flight through reduced drag but imposes an increasedaerodynamic demand for hovering by degrading lift productionand simultaneously elevating the induced power requirementsof flight. This effect has been well-studied in the hoveringflight of hummingbirds, which occur throughout high-elevationhabitats in the western hemisphere. Phylogenetically controlledstudies have shown that hummingbirds compensate morphologicallyfor such hypodense air through relative increases in wing size,and kinematically via increased stroke amplitude during thewingbeat. Such compensatory mechanisms result in fairly constantpower requirements for hovering at different elevations, butdecrease the margin of excess power available for other flightbehaviors.     

Evidence supportive of impaired myocardial blood flow reserve at high altitude in subjects developing high-altitude pulmonary edema

An exaggerated increase in pulmonary arterial pressure is the hallmark of high-altitude pulmonary edema (HAPE) and is associated with endothelial dysfunction of the pulmonary vasculature. Whether the myocardial circulation is affected as well is not known. The aim of this study was, therefore, to investigate whether myocardial blood flow reserve (MBFr) is altered in mountaineers developing HAPE. Healthy mountaineers taking part in a trial of prophylactic treatment of HAPE were examined at low (490 m) and high altitude (4,559 m). MBFr was derived from low mechanical index contrast echocardiography, performed at rest and during submaximal exercise. Among 24 subjects evaluated for MBFr, 9 were HAPE-susceptible individuals on prophylactic treatment with dexamethasone or tadalafil, 6 were HAPE-susceptible individuals on placebo, and 9 persons without HAPE susceptibility served as controls. At low altitude, MBFr did not differ between groups. At high altitude, MBFr increased significantly in HAPE-susceptible individuals on treatment (from 2.2 +/- 0.8 at low to 2.9 +/- 1.0 at high altitude, P = 0.04) and in control persons (from 1.9 +/- 0.8 to 2.8 +/- 1.0, P = 0.02), but not in HAPE-susceptible individuals on placebo (2.5 +/- 0.3 and 2.0 +/- 1.3 at low and high altitude, respectively, P > 0.1). The response to high altitude was significantly different between the two groups (P = 0.01). There was a significant inverse relation between the increase in the pressure gradient across the tricuspid valve and the change in myocardial blood flow reserve. HAPE-susceptible individuals not taking prophylactic treatment exhibit a reduced MBFr compared with either treated HAPE-susceptible individuals or healthy controls at high altitude.     

Edema from cyclooxygenase products of endogenous arachidonic acid in isolated lung

We infused A23187, a calcium ionophore, into the pulmonary circulation of dextran-salt-perfused isolated rabbit lungs to release endogenous arachidonic acid. This led to elevations in pulmonary arterial pressure and to pulmonary edema as measured by extravascular wet-to-dry weight ratios. The increase in pressure and edema was prevented by indomethacin, a cyclooxygenase enzyme inhibitor, and by 1-benzylimidazole, a selective inhibitor of thromboxane (Tx) A2 synthesis. Transvascular flux of 125I-albumin from vascular to extravascular spaces of the lung was not elevated by A23187 but was elevated by infusion of oleic acid, an agent known to produce permeability pulmonary edema. We confirmed that A23187 leads to elevations in cyclooxygenase products and that indomethacin and 1-benzylimidazole inhibit synthesis of all cyclooxygenase products and TxA2, respectively, by measuring perfusate levels of prostaglandin (PG) I2 as 6-ketoprostaglandin F1 alpha, PGE2, and PGF2 alpha and TxA2 as TxB2. We conclude that release of endogenous pulmonary arachidonic acid can lead to pulmonary edema from conversion of such arachidonic acid to cyclooxygenase products, most notably TxA2. This edema was most likely from a net hydrostatic accumulation of extravascular lung water with an unchanged permeability of the vascular space, since an index of permeability-surface area product (i.e., transvascular albumin flux) was not increased.     

Association of Arterial Oxygen Saturation and Acute Mountain Sickness Susceptibility: A Meta-analysis

Acute mountain sickness (AMS) is the most common high altitude illnesses experienced during rapid ascent to a higher altitude without prior acclimation. It is mainly characterized by a headache which may be accompanied with nausea, vomiting, anorexia, dizziness, lethargy, fatigue, and sleep disturbance. If not diagnosed and treated in a timely manner, AMS can develop into deadly high altitude pulmonary edema or high altitude cerebral edema. In the previous studies of individual variation in susceptibility to AMS, arterial oxygen saturation ( \(S_{{{\text{O}}_{2} }}\) ) was identified as being associated with AMS. However, other studies have reported no association between AMS and arterial oxygen saturation. In this study, the association between \(S_{{{\text{O}}_{2} }}\) and AMS was assessed through a meta-analysis of published data. The literature databases PubMed, Web of Science, LWW, Science Direct, and Embase were queried for papers published before 15 April 2014. A fixed-effects model and a random-effects model were applied (Revman 5.0) on the basis of heterogeneity, and the study quality was assessed in duplicate. Twelve studies with 614 AMS patients and 1,025 control subjects were analyzed. There was a significant association with differences in \(S_{{{\text{O}}_{2} }}\) and the risk of developing AMS. \(S_{{{\text{O}}_{2} }}\) values are associated with AMS incidence.     

Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition

Hypoxic pulmonary vasoconstriction (HPV) occurs with ascent to high altitude and can contribute to development of high altitude pulmonary edema (HAPE). Vascular smooth muscle contains carbonic anhydrase (CA), and acetazolamide (AZ), a CA inhibitor, blunts HPV and might be useful in the prevention of HAPE. The mechanism by which AZ impairs HPV is uncertain. Originally developed as a diuretic, AZ also has direct effects on systemic vascular smooth muscle, including modulation of pH and membrane potential; however, the effect of AZ on pulmonary arterial smooth muscle cells (PASMCs) is unknown. Since HPV requires Ca2+ influx into PASMCs and can be modulated by pH, we hypothesized that AZ alters hypoxia-induced changes in PASMC intracellular pH (pH(i)) or Ca2+ concentration ([Ca2+](i)). Using fluorescent microscopy, we tested the effect of AZ as well as two other potent CA inhibitors, benzolamide and ethoxzolamide, which exhibit low and high membrane permeability, respectively, on hypoxia-induced responses in PASMCs. Hypoxia caused a significant increase in [Ca2+](i) but no change in pH(i). All three CA inhibitors slightly decreased basal pH(i), but only AZ caused a concentration-dependent decrease in the [Ca2+](i) response to hypoxia. AZ had no effect on the KCl-induced increase in [Ca2+](i) or membrane potential. N-methyl-AZ, a synthesized compound lacking the unsubstituted sulfonamide group required for CA inhibition, had no effect on pH(i) but inhibited hypoxia-induced Ca2+ responses. These results suggest that AZ attenuates HPV by selectively inhibiting hypoxia-induced Ca2+ responses via a mechanism independent of CA inhibition, changes in pH(i), or membrane potential.     

急性高原病的遗传易感性

急性高原病(Acute high altitude disease, AHAD)分为急性高原反应、高原肺水肿和高原脑水肿, 是高原特发病之一, 在高原旅居者中(>2 500 m)具有高发生率, 不仅影响人们的工作能力和健康, 而且可能危及生命。尽管AHAD的相关研究已开展百余年, 其病理生理机制仍不明确, 但大量研究已证实AHAD存在易感性的差异。文章综述了迄今为止AHAD的遗传易感性研究进展, 以期为AHAD的流行病学研究提供有益的参考资料。     

Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema.

Strenuous exercise may be a significant contributing factor for development of high-altitude pulmonary edema, particularly at low or moderate altitudes. Thus we investigated the effects of heavy cycle ergometer exercise (90% maximal effort) under hypoxic conditions in which the combined effects of a marked increase in pulmonary blood flow and nonuniform hypoxic pulmonary vasoconstriction could add significantly to augment the mechanical stress on the pulmonary microcirculation. We postulated that intense exercise at altitude would result in an augmented permeability edema. We recruited eight endurance athletes and examined their bronchoalveolar lavage fluid (BALF) for red blood cells (RBCs), protein, inflammatory cells, and soluble mediators at 2 and 26 h after intense exercise under normoxic and hypoxic conditions. After heavy exercise, under all conditions, the athletes developed a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. We found that exercise at altitude (3,810 m) caused significantly greater leakage of RBCs [9.2 (SD 3.1)x10(4) cells/ml] into the alveolar space than that seen with normoxic exercise [5.4 (SD 1.2)x10(4) cells/ml]. At altitude, the 26-h postexercise BALF revealed significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. Interestingly, the BALF profiles following exercise at altitude are similar to that of early high-altitude pulmonary edema. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.     

Pathophysiological significance of peroxidative stress, neuronal damage, and membrane permeability in acute mountain sickness.

Free radical-mediated changes in vascular permeability and subsequent inflammatory response may be a contributory pathogenetic cofactor responsible for the development of neurological sequelae associated with acute mountain sickness (AMS). To investigate this, 49 subjects were examined at sea level and serially after rapid ascent to 4,559 m. Although the venous concentration of total creatine phosphokinase activity was measured in all subjects, a complementary examination of lipid peroxidation (F(2)-isoprostanes), inflammatory (TNF-alpha, IL-1beta, IL-2, IL-6, IL-8, C-reactive protein), and cerebrovascular tissue damage (neuron-specific enolase) biomarkers was confined to a subcohort of 24 subjects. A selective increase (P < 0.05) in total creatine phosphokinase was observed in subjects diagnosed with AMS at high altitude (n = 25) compared with apparently healthy controls (n = 24). However, despite a marked increase in IL-6 and C-reactive protein attributable primarily to subjects developing high-altitude pulmonary edema, subcohort analyses demonstrated no selective differences in F(2)-isoprostanes, neuron-specific enolase, or remaining proinflammatory cytokines due to AMS (n = 14). The present findings are the first to demonstrate that free radical-mediated neuronal damage of sufficient degree to be detected in the peripheral circulation does not occur and is, therefore, unlikely to be an important, initiating event that is critical for the development of AMS. The pathophysiological significance of increased sarcolemmal membrane permeability and inflammatory response, either as a cause or epiphenomenon of AMS and/or high-altitude pulmonary edema, remains to be elucidated.     

中国汉族高原肺水肿易感基因的全基因组关联研究

高原肺水肿(High-altitude pulmonary edema, HAPE)是一种特发于高原低氧环境的肺水肿, 是遗传和环境因素共同作用的结果。为了寻找与中国汉族高原肺水肿相关的单核苷酸多态性(Single nucleotide polymorphism, SNP)位点及易感基因, 文章利用Affymetrix SNP Array 6.0芯片, 对2010年5月至2012年7月在青海省玉树地区执行援建任务时来自平原地区的40例HAPE患者和33例健康对照进行全基因组SNP分型, 通过PLINK软件对芯片结果进行全基因组关联分析(Genome-wide association study, GWAS), 筛选出在病例组和对照组中间有显著差异(P < 10E-7)的SNP位点57个, 通过对57个SNP位点附近74个基因进行GO与Pathway富集分析, 发现这些基因与“前列腺素代谢”、“四烯酸代谢”、“氮代谢”显著相关(adjust P < 0.05), 以上代谢过程与HAPE病理生理机制相关。结果表明, 高原肺水肿受遗传多态性影响, 与多个基因以及位点相关。