Development Of High-altitude Pulmonary Edema Research Articles

Long noncoding RNA ANRIL alleviates hypoxia-induced pulmonary microvascular endothelial cell damage.

High-altitude pulmonary oedema (HAPE) is a form of noncardiogenic pulmonary oedema. Studies have found that long noncoding RNA (lncRNA) plays an important role in HAPE. ANRIL is significant in pulmonary illnesses, which implies that alterations in ANRIL expression levels may be involved in the beginning and development of HAPE. However, the specific mechanism is indistinct. The present study is meant to explore the effect and mechanism of ANRIL on hypoxic-induced injury of pulmonary microvascular endothelial cells (PMEVCs). In the hypoxic model of PMVECs, overexpression of ANRIL or knockdown of miR-181c-5p was performed to assess cell proliferation, apoptosis, and migration. Furthermore, the levels of apoptosis-related proteins, inflammatory factors, and vascular active factors were also measured. The results showed that, after 24 h of hypoxia, PMVECs proliferation and migration were suppressed in comparison to the control group, along with an increase in apoptosis, a decrease in the expression of ANRIL, and an increase in the expression of miR-181c-5p (all p < .05). The damage caused by hypoxia in PMVECs can be lessened by overexpressing ANRIL, which also inhibits the production of TNF-α, iNOS, and VEGF as well as BAX and cleaved caspase-3 (all p < .05). Further experimental results showed that overexpression of ANRIL and knockdown of miR-181c-5p had the same protection against hypoxic injury in PMVECs (all p < .05). Our study suggests that ANRIL may prevent hypoxia injury to PMVECs in HAPE through the negative regulation of miR-181c-5p.

Role of neutrophil myeloperoxidase in the development and progression of high-altitude pulmonary edema

BackgroundNeutrophil infiltration and hypoxic pulmonary vasoconstriction induced by hypobaric hypoxic stress are vital in high-altitude pulmonary edema (HAPE). Myeloperoxidase (MPO), an important enzyme in neutrophils, is associated with inflammation and oxidative stress and is also involved in the regulation of nitric oxide synthase (NOS), an enzyme that catalyzes the production of the vasodilatory factor nitric oxide (NO). However, the role of neutrophil MPO in HAPE's progression is still uncertain. Therefore, we hypothesize that MPO is involved in the development of HAPE via NOS. MethodsIn Xining, China (altitude: 2260 m), C57BL/6 N wild-type and mpo−/− mice served as normoxic controls, while a hypobaric chamber simulated 7000 m altitude for hypoxia. L-NAME, a nitric oxide synthase (NOS) inhibitor to inhibit NO production, was the experimental drug, and D-NAME, without NOS inhibitory effects, was the control. After measuring pulmonary artery pressure (PAP), samples were collected and analyzed for blood neutrophils, oxidative stress, inflammation, vasoactive substances, pulmonary alveolar-capillary barrier permeability, and lung tissue morphology. ResultsWild-type mice's lung injury scores, permeability, and neutrophil counts rose at 24 and 48 h of hypoxia exposure. Under hypoxia, PAP increased from 12.89 ± 1.51 mmHg under normoxia to 20.62 ± 3.33 mmHg significantly in wild-type mice and from 13.24 ± 0.79 mmHg to 16.50 ± 2.07 mmHg in mpo−/− mice. Consistent with PAP, inducible NOS activity, lung permeability, lung injury scores, oxidative stress response, and inflammation showed more significant increases in wild-type mice than in mpo−/− mice. Additionally, endothelial NOS activity and NO levels decreased more pronouncedly in wild-type mice than in mpo−/− mice. NOS inhibition during hypoxia led to more significant increases in PAP, permeability, and lung injury scores compared to the drug control group, especially in wild-type mice. ConclusionMPO knockout reduces oxidative stress and inflammation to preserve alveolar-capillary barrier permeability and limits the decline in endothelial NOS activity to reduce PAP elevation during hypoxia. MPO inhibition emerges as a prospective therapeutic strategy for HAPE, offering avenues for precise interventions.

Performance and reliability of two frequently used point-of-care blood gas analyzers at 423 and 4,559 m

Background and ObjectivesBlood gas analyzers (BGA) aid medical decision-making. Their specified performance criteria are based on sea level conditions. However, millions of people are living at high altitude (HA) where the performance of BGAs is poorly characterized. We investigated the effect of exposure to 4,559 m on the reliability and robustness of two BGAs widely used at HA. MethodsIn this prospective study arterial blood samples from 13 volunteers (2 female) with susceptibility to the development of high-altitude pulmonary edema were collected once near sea level at 423 m (nSL423) and three times at high altitude (HA4,559). Samples were measured in triplicate with the cartridge BGAs Rapidpoint 500 (SIE; Siemens Healthcare) and the ABL90 (RAD; Radiometer) to calculate coefficients of variation (CV) and intraclass correlation coefficients (ICC) within a mixed model. ResultsAt nSL423 and HA4,559, 3% and 17% of all data were not reported with SIE, mainly due to clotting of the sample caused by delays because of the frequent automated calibration routines. No data were missing with RAD. ICCs were not significantly lower (mean (min–max) 0.87 (0.68–0.98) vs. 0.94 (0.84–1.00); p = 0.217) with SIE at nSL423, but significantly lower at HA4,559 (0.87 (0.49–1.00) vs. 0.99 (0.96–1.00); p = 0.025). All CVs, except that for arterial oxygen saturation at HA4,559,were higher with SIE . ConclusionIn this study, the reliability of RAD was superior to SIE at nSL423 and HA4,559. In contrast to RAD, the performance of SIE declined at HA4,559. SIE was more prone to not reporting all variables, especially at HA4559.

Unique mutations in mitochondrial DNA and associated pathways involved in high altitude pulmonary edema susceptibility in Indian lowlanders

High altitude pulmonary edema (HAPE) is a life threatening non-cardiogenic pulmonary edema that occurs in an otherwise healthy individuals travelling to altitude above 2500 m. Earlier studies have reported association of mutations in nuclear (nDNA) and mitochondrial DNA (mtDNA) with HAPE susceptibility. However, the molecular mechanisms involved in the pathobiology of HAPE have not been fully understood. The present study investigates the genetic predisposition to HAPE by analyzing the mtDNA mutations in HAPE susceptibles (n = 23) and acclimatized controls (n = 23) using next generation sequencing. Structural analysis of mutations was done using SWISS Model server and stability was determined using ΔΔG values. Meta-analysis of GSE52209 dataset was done to identify differentially expressed genes (DEGs) in HAPE susceptibles and acclimatized controls. Fourteen non-synonymous, conserved and pathogenic mutations were predicted using SIFT and PolyPhen scoring in protein coding genes, whereas six mutations in mt-tRNA genes showed association with HAPE (p ≤ 0.05). The structural analysis of these mutations revealed conformational changes in critical regions in Complexes I–V which are involved in subunit assembly and proton pumping activity. The protein–protein interaction network analysis of DEGs showed that HIF1α, EGLN2, EGLN3, PDK1, TFAM, PPARGC1α and NRF1 genes form highly interconnected cluster. Further, pathway enrichment analysis using DAVID revealed that “HIF-1 signaling”, “oxidative phosphorylation” and “Metabolic pathways” had strong association with HAPE. Based on the findings it appears that the identified mtDNA mutations may be a potential risk factor in development of HAPE with the associated pathways providing mechanistic insight into the understanding of pathobiology of HAPE and sites for development of therapeutic targets. Communicated by Ramaswamy H. Sarma

Acetazolamide prevents hypoxia-induced reactive oxygen species generation and calcium release in pulmonary arterial smooth muscle.

Upon sensing a reduction in local oxygen partial pressure, pulmonary vessels constrict, a phenomenon known as hypoxic pulmonary vasoconstriction. Excessive hypoxic pulmonary vasoconstriction can occur with ascent to high altitude and is a contributing factor to the development of high-altitude pulmonary edema. The carbonic anhydrase inhibitor, acetazolamide, attenuates hypoxic pulmonary vasoconstriction through stimulation of alveolar ventilation via modulation of acid–base homeostasis and by direct effects on pulmonary vascular smooth muscle. In pulmonary arterial smooth muscle cells (PASMCs), acetazolamide prevents hypoxia-induced increases in intracellular calcium concentration ([Ca2+]i), although the exact mechanism by which this occurs is unknown. In this study, we explored the effect of acetazolamide on various calcium-handling pathways in PASMCs. Using fluorescent microscopy, we tested whether acetazolamide directly inhibited store-operated calcium entry or calcium release from the sarcoplasmic reticulum, two well-documented sources of hypoxia-induced increases in [Ca2+]i in PASMCs. Acetazolamide had no effect on calcium entry stimulated by store-depletion, nor on calcium release from the sarcoplasmic reticulum induced by either phenylephrine to activate inositol triphosphate receptors or caffeine to activate ryanodine receptors. In contrast, acetazolamide completely prevented Ca2+-release from the sarcoplasmic reticulum induced by hypoxia (4% O2). Since these results suggest the acetazolamide interferes with a mechanism upstream of the inositol triphosphate and ryanodine receptors, we also determined whether acetazolamide might prevent hypoxia-induced changes in reactive oxygen species production. Using roGFP, a ratiometric reactive oxygen species-sensitive fluorescent probe, we found that hypoxia caused a significant increase in reactive oxygen species in PASMCs that was prevented by 100 μM acetazolamide. Together, these results suggest that acetazolamide prevents hypoxia-induced changes in [Ca2+]i by attenuating reactive oxygen species production and subsequent activation of Ca2+-release from sarcoplasmic reticulum stores.

Early hours in the development of high-altitude pulmonary edema: time course and mechanisms.

Clinically evident high-altitude pulmonary edema (HAPE) is characterized by severe cyanosis, dyspnea, cough, and difficulty with physical exertion. This usually occurs within 1-2 days of ascent often with the additional stresses of any exercise and hypoventilation of sleep. The earliest events in evolving HAPE progress through clinically silent and then minimally recognized problems. The most important of these events involves an exaggerated elevation of pulmonary artery (PA) pressure in response to the ambient hypoxia. Hypoxic pulmonary vasoconstriction (HPV) is a rapid response with several phases. The first phase in both resistance arterioles and venules occurs within 5-10 min. This is followed by a second phase that further raises PA pressure by another 100% over the next 2-8 h. Combined with vasoconstriction and likely an unevenness in the regional strength of HPV, pressures in some microvascular regions with lesser arterial constriction rise to a level that initiates greater filtration of fluid into the interstitium. As pressures continue to rise local lymphatic clearance rates are exceeded and interstitial fluid begins to accumulate. Beyond elevation of transmural pressure gradients there is a dynamic noninjurious relaxation of microvascular and epithelial cell-cell contacts and an increase in transcellular vesicular transport which accelerate leakage. At some point with further pressure elevation, damage occurs with breaks of the barrier and bleeding into the alveolar space, a late-stage situation termed capillary stress failure. Earlier before there is fluid accumulation, alveolar hypoxia and hyperventilation-induced hypocapnia reduce the capacity of the alveolar epithelium to reabsorb sodium and water back into the interstitial space. More modest ascent which slows the rate of rise in PA pressure and allows for adaptive remodeling of the microvasculature, drugs which lower PA pressure, and those that can enhance fluid reabsorption will all forestall the deleterious early rise of microvascular pressures and diminished active alveolar fluid reabsorption that precede and underlie the development of HAPE.

Susceptibility to high-altitude pulmonary edema is associated with increased pulmonary arterial stiffness during exercise.

High-altitude pulmonary edema (HAPE), a reversible form of capillary leak, is a common consequence of rapid ascension to high altitude and a major cause of death related to high-altitude exposure. Individuals with a prior history of HAPE are more susceptible to future episodes, but the underlying risk factors remain uncertain. Previous studies have shown that HAPE-susceptible subjects have an exaggerated pulmonary vasoreactivity to acute hypoxia, but incomplete data are available regarding their vascular response to exercise. To examine this, seven HAPE-susceptible subjects and nine control subjects (HAPE-resistant) were studied at rest and during incremental exercise at sea level and at 3,810 m altitude. Studies were conducted in both normoxic (inspired Po2 = 148 Torr) and hypoxic (inspired Po2 = 91 Torr) conditions at each location. Here, we report an expanded analysis of previously published data, including a distensible vessel model that showed that HAPE-susceptible subjects had significantly reduced small distal artery distensibility at sea level compared with HAPE-resistant control subjects [0.011 ± 0.001 vs. 0.021 ± 0.002 mmHg-1; P < 0.001). Moreover, HAPE-susceptible subjects demonstrated constant distensibility over all conditions, suggesting that distal arteries are maximally distended at rest. Consistent with having increased distal artery stiffness, HAPE-susceptible subjects had greater increases in pulmonary artery pulse pressure with exercise, which suggests increased proximal artery stiffness. In summary, HAPE-susceptible subjects have exercise-induced increases in proximal artery stiffness and baseline increases in distal artery stiffness, suggesting increased pulsatile load on the right ventricle.NEW & NOTEWORTHY In comparison to subjects who appear resistant to high-altitude pulmonary edema, those previously symptomatic show greater increases in large and small artery stiffness in response to exercise. These differences in arterial stiffness may be a risk factor for the development of high-altitude pulmonary edema or evidence that consequences of high-altitude pulmonary edema are long-lasting after return to sea level.

A case-control study of the genetic polymorphism of IL6 and HAPE risk in a Chinese Han population.

The role of inflammatory cytokines in High-altitude pulmonary edema (HAPE) remains unclear. The purpose of this study was to evaluate the role of IL4 and IL6 gene polymorphism in the development of HAPE in Chinese people. In the present study, we screened ten polymorphisms of IL4 and IL6 gene in 265 HAPE and 303 healthy volunteers. Genotypes were determined using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. Two single-nucleotide polymorphisms (SNPs) in the IL6 gene were significantly associated with HAPE. Rs1800796 and rs1524107 (G vs C, OR=1.31, 95%CI=1.01-1.69, P=.041 and T vs C, OR=1.35, 95%CI=1.05-1.74, P=.020, respectively). However, there did not found any association for IL4 gene. Inflammatory cytokines may play a role in the progress of HAPE. These polymorphisms could be genetic markers for predicting the susceptibility to HAPE.

Angiotensin II receptor 1 gene variants are associated with high-altitude pulmonary edema risk.

Previous studies demonstrated that Angiotensin II Receptor 1 (AGTR1) may play an important role in the development of high-altitude pulmonary edema. We envisaged a role for AGTR1 gene variants in the pathogenesis of HAPE and investigated their potential associations with HAPE in a Han Chinese population. We genotyped seven AGTR1 polymorphisms in 267 patients with diagnosed HAPE and 304 controls and evaluated their association with risk of HAPE. Statistically significant associations were found for the single nucleotide polymorphisms (SNPs) rs275651 (p = 0.017; odds ratio [OR] = 0.65) and rs275652 (p = 0.016; OR = 0.64). Another SNP rs10941679 showed a marginally significant association after adjusting for age and sex in the additive genetic model (adjusted OR = 1.44, 95% CI = 1.01-2.04, p = 0.040). Haplotype analysis confirmed that the haplotype “AG” was associated with a 35% reduction in the risk of developing HAPE, while the haplotype “AA” increased the risk of developing HAPE by 44%. These results provide the first evidence linking genetic variations in AGTR1 with HAPE risk in Han Chinese individuals.

Positive Association of D Allele of ACE Gene With High Altitude Pulmonary Edema in Indian Population

High altitude pulmonary edema (HAPE) is a potentially fatal high altitude illness occurring as a result of hypobaric hypoxia with an unknown underlying genetic mechanism. Recent studies have shown a possible association between HAPE and polymorphisms in genes of the renin-angiotensin-aldosterone system (RAAS), which play a key role in sensitivity of an individual toward HAPE. For the present investigation, study groups consisted of HAPE patients (HAPE) and acclimatized control subjects (rCON). Four single-nucleotide polymorphisms (SNPs) were genotyped using restriction fragment length polymorphism (RFLP) analysis in genes of the RAAS pathway, specifically, renin (REN) C(-4063)T (rs41317140) and RENi8-83 (rs2368564), angiotensin (AGT) M(235)T (rs699), and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) (rs1799752). Only the I/D polymorphism of the ACE gene showed a significant difference between the HAPE and rCON groups. The frequency of the D allele was found to be significantly higher in the HAPE group. Arterial oxygen saturation levels were significantly lower in the HAPE group compared with the rCON group and also decreased in the I/D and D/D genotypes compared with the I/I genotype in these groups. The other polymorphisms occurring in the REN and AGT genes were not significantly different between the 2 groups. These findings demonstrate a possible association of the I/D polymorphism of the ACE gene with the development of HAPE, with D/D being the at-risk genotype.

Genetic Variations in Renin-Angiotensin-Aldosterone System (RAAS) Genes Could Contribute to High Altitude Pulmonary Edema: Review

Background: At High Altitude (HA) (elevation >2500m), inevitable hypobaric hypoxia leads to development of symptoms associated with low oxygen pressure in many non acclimatized sojourners which includes severe forms of altitude mountain sickness (AMS) such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). These syndromes are reportedly less common in high altitude native population than in lowlanders which can be attributed to genetic adaptations that have taken place over generations. Methods: Numerous genetic studies have been associated with hypoxic adaptation and susceptibility to high altitude conditions. An increased pulmonary arterial pressure (PAP) and fluid loss has been observed in all forms of AMS with varied intensity. Since renin-angiotensin-aldosterone system (RAAS) has a critical function of maintaining homeostasis in closed circulatory system, the polymorphisms occurring in the genes of RAAS pathway could likely be contributing towards acclimatization/mal-adaptation to high altitude maladies. In view of above, this review has been compiled to associate the genetic variations in RAAS with adaptation/acclimatization to high altitude conditions. Results: Studies conducted so far relate allele frequencies of polymorphic loci in genes encoding components of RAAS pathway such as angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin receptors (AT1) and aldosterone synthase (CYP11B2) and associate them with hypertension, regulation of blood pressure and maintenance of osmotic balance in the body. Conclusions: In this review, various studies have been put together comprehensively indicating the involvement of genetic variants of RAAS genes in resistance or sensitivity of an individual towards development of HAPE.

ROUTINE TRANSESOPHAGEAL ECHO PRIOR TO ATRIAL FIBRILLATION/FLUTTER ABLATIONS IN LOW RISK PATIENTS - ARE THEY NECESSARY?

BACKGROUND: The physiopathology and determinants of high altitude pulmonary edema (HAPE) remain ill defined, but increased hypoxia-related pre-capillary pulmonary artery pressure (PAP) has been shown as a key component. No parameter has been validated to predict the development of HAPE among recreational climbers. We aimed to assess whether baseline right ventricular (RV) echocardiographic indices were predictive of an increased hypoxic PAP response. METHODS: 14healthy lowlander subjects (8men; ages 27-65 years old) were assessed by echocardiography at sea level (Montreal) and at 3450m (Namche Bazaar) and 4730m (Chukkung) during an expedition in the Khumbu Valley, Nepal. Baseline RV performance parameterswere analysed and compared to the systolic PAP maximal increment observed at high altitude; correlation coefficient (r) and coefficient of determination (r2) were calculated. RESULTS: At high altitude, none of the subjects had clinical criteria for HAPE, although all except one had ultrasound signs of interstitial lung water. Systolic PAP increased in all subjects between Montreal and Chukkung (mean PAP 27.4 +/5.4 mmHg vs. 39.3 +/7.7mmHg respectively; p<0.001). Sea level RV Tei index assessed by tissue doppler was moderately correlated to the PAP increment (r21⁄4 0.37), as was the s’ velocity at the tricuspid annulus (r2 1⁄4 0.27). Baseline Tricuspid Annular Plane Systolic Excursion (TAPSE) was strongly correlated to the PAP increment (fig. 1). The tricuspid E/e’ showed no correlation with PAP altitude-induced increment. RV free wall longitudinal strain was assessed and, although baseline value did not correlate with PAP increment (r21⁄4 0.05), strain increment betweenMontreal and Chukkung was moderately correlated to the PAP reached at the highest altitude (r2 1⁄4 0.39). CONCLUSION: RV echocardiographic indices such as TAPSE, s’ and Tei index at sea level correlate to the level at which PAP increases in lowlanders after a sub-acute ascent to high altitude. These findings reinforce the role of RV function in the development of high altitude pulmonary diseases and, should they be confirmed on a larger population, suggest that these indices could help counsel lowlanders before attempting high-altitude climbs. 315 ROUTINE TRANSESOPHAGEAL ECHO PRIOR TO ATRIAL FIBRILLATION/FLUTTER ABLATIONS IN LOW RISK PATIENTS ARE THEY NECESSARY?

Effects of ambient pressure on pulmonary nitric oxide

Airway nitric oxide (NO) has been proposed to play a role in the development of high-altitude pulmonary edema. We undertook a study of the effects of acute changes of ambient pressure on exhaled and alveolar NO in the range 0.5-4 atmospheres absolute (ATA, 379-3,040 mmHg) in eight healthy subjects breathing normoxic nitrogen-oxygen mixtures. On the basis of previous work with inhalation of low-density helium-oxygen gas, we expected facilitated backdiffusion and lowered exhaled NO at 0.5 ATA and the opposite at 4 ATA. Instead, the exhaled NO partial pressure (Pe(NO)) did not differ between pressures and averaged 1.21 ± 0.16 (SE) mPa across pressures. As a consequence, exhaled NO fractions varied inversely with pressure. Alveolar estimates of the NO partial pressure differed between pressures and averaged 88 (P = 0.04) and 176 (P = 0.009) percent of control (1 ATA) at 0.5 and 4 ATA, respectively. The airway contribution to exhaled NO was reduced to 79% of control (P = 0.009) at 4 ATA. Our finding of the same Pe(NO) at 0.5 and 1 ATA is at variance with previous findings of a reduced Pe(NO) with inhalation of low-density gas at normal pressure, and this discrepancy may be due to the much longer durations of low-density gas breathing in the present study compared with previous studies with helium-oxygen breathing. The present data are compatible with the notion of an enhanced convective backtransport of NO, compensating for attenuated backdiffusion of NO with increasing pressure. An alternative interpretation is a pressure-induced suppression of NO formation in the airways.

Association of polymorphisms in angiotensin and aldosterone synthase genes of the renin–angiotensin–aldosterone system with high-altitude pulmonary edema

Studies on different populations have suggested variability in individual susceptibility to altitude sickness depending on genetic makeup. The renin-angiotensin-aldosterone system (RAAS) pathway plays a key role in regulation of vascular tone and circulatory homeostasis. The present study was undertaken to investigate the possible association of the RAAS in the development of high-altitude pulmonary edema (HAPE) in lowlanders exposed to high altitude. Three categories of subjects were selected: individuals who developed HAPE on acute induction to high altitude (HAPE); individuals tolerant to high-altitude exposure who showed no symptoms of HAPE (resistant controls; rCON); and natives of high altitude (HAN). Genetic variants in the genes of the RAAS such as renin (REN), angiotensin (AGT), angiotensin-converting enzyme (ACE), aldosterone synthase (CYP11B2) and angiotensin II receptor type 1 (AGTR1) have been investigated. The T174M polymorphism in AGT showed a significant difference in HAPE and HAN and also HAN and controls. Also, genotyping in the CYP11B2 T-344C promoter region resulted in a significant difference between HAPE and HAN both at genotypic and allelic levels. The genotypic difference was statistically insignificant for the AGTR1 A1166C 3' UTR. The present investigation demonstrates a possible association between the polymorphisms existing in the RAAS pathway T174M and CYP11B2 C-344T and sensitivity of an individual to develop HAPE. The results also indicate the existence of ethnic variation between the HAN and the other two groups comprising lowlanders.

Stress failure and high-altitude pulmonary oedema: mechanistic insights from physiology

High-altitude pulmonary oedema (HAPE) is a potentially fatal altitude illness affecting individuals within 2–4 days of rapid ascent to altitudes above 3,000 m. Although a minority of high-altitude travellers develop HAPE 1, there is some suggestion that many develop subclinical fluid accumulation without overt alveolar flooding 2. The inciting mechanism of the injury to the lung in HAPE still generates some controversy. However, there is an ever-growing body of evidence that mechanical injury to the pulmonary capillaries induced by high transmural pressures starts a cascade of events that ultimately results in the development of HAPE. This injury, termed “stress failure” described by West et al. 3, refers to mechanically induced breaks in the blood-gas barrier, and these have been suggested to be important the pathophysiology of a number of human diseases 4. In animals, when pulmonary capillaries are subjected to increased transmural pressure, ultrastructural changes consisting of discrete areas of damage to the blood–gas barrier, with rupture of the capillary endothelium, extracellular matrix and the alveolar epithelium, interspersed with large areas of structurally intact blood–gas barrier are observed 5. Accompanying this is increased permeability of the lung to protein and red blood cells, as measured by increased concentrations in bronchoalveolar lavage fluid 6. Leukotriene (LT)B4 concentration is also increased in bronchoalveolar lavage fluid 6, perhaps representing cellular activation by exposed basement membrane. Similar findings are observed in some humans following maximal exercise in normoxia 7 where bronchoalveolar lavage fluid contains increased concentrations of red cells, protein and LTB4 thought to result from high pulmonary capillary pressures. In both of these instances, the blood–gas barrier retains sieving function for large molecular weight proteins 6. However, in established HAPE, permeability to macromolecules is increased 8, and an inflammatory response of the lung to …

High-altitude pulmonary edema in Japan

To understand the pathophysiology of high-altitude pulmonary edema (HAPE), we examined the pathway of adaptation to high altitude in lifelong of Tibet. The Tibetan natives had higher exercise performance, but lower maximal oxygen uptake and lower blood lactate concentrations than did acclimatized Han newcomers. Clinical and basic studies done to determine the pathophysiologic characteristics of 47 patients with HAPE and of subjects susceptible to HAPE. The altitude of onset was 2,680 m to 3,190 m above sea level. Results of hemodynamic studies and the presence of protein-rich edema fluid indicated that HAPE is noncardiogenic and is a type of increased permeability edema. The levels of IL-1 beta, IL-6, IL-8, and TNF-alpha in bronchoalveolar lavage fluid from subjects with HAPE were high on admission. The subjects susceptible to HAPE had much greater increases in an index of pulmonary vascular resistance than did the controls, which resulted in much higher levels of pulmonary arterial pressure during both acute hypoxia and hypobaria. The subjects susceptible to HAPE also has blunted hypoxic ventilatory drives. We studied whether human leukocyte antigen DR-6 functions as a genetic predisposition to HAPE. The frequency of DR-6 was increased in the subjects susceptible to HAPE, which suggests that they have a constitutional abnormality in the pulmonary circulatory, and ventilatory responses to hypoxia and hypobaria, and that genetic factors may be involved in the development of HAPE.

Stress failure plays a major role in the development of high-altitude pulmonary oedema in rats

Hypoxia and exertion are considered as the two main factors in the development of high-altitude pulmonary oedema (HAPE), however its pathophysiology remains unclear. Therefore, we established a model in which 32 Sprague-Dawley rats were randomly assigned to normoxic rest, hypoxic rest, normoxic exercise and hypoxic exercise. An altitude of 4,700 m was simulated using hypobaric hypoxia, while exercise consisted 48 h walk with 15-20 min breaks every 4 h. Arterial blood gas, bronchoalveolar lavage (BAL), lung wet-to-dry weight (W/D) ratio and histological measurements were conducted on each animal. In rats exercising in hypoxia, BAL protein and lung W/D ratio were significantly increased but no changes in BAL leukotriene B(4) and immunoglobulin M were observed. In the same group, lung histology showed typical haemorrhagic lung oedema and disruption of both alveolar epithelium and capillary endothelium while hypoxia or exertion alone only induced slight endothelium and epithelium swelling/disruption. Our study established a direct link between histological and physiological evidence of HAPE-like symptoms and we demonstrated that hypoxia and exertion can synergistically induce HAPE-like symptoms in Sprague-Dawley rats without inducing lung inflammation. We therefore propose that alveolar epithelium and capillary endothelium stress failure play a major role in the development of HAPE.

Genetic interaction of Hsp70 family genes polymorphisms with high-altitude pulmonary edema among Chinese railway constructors at altitudes exceeding 4000 meters

Background High-altitude pulmonary edema (HAPE) is thought of as an independent clinical disorder with a constitutional or genetic component in its etiology. We focused on 5 common polymorphisms within HSPA1A (rs1043618 and rs1008438), HSPA1B (rs1061581 and rs539689) and HSPA1L (rs2227956) of Hsp70 family to explore their potential interaction upon susceptibility to HAPE in Chinese. Methods A total of 148 HAPE patients and 483 matched controls were recruited during the construction of Qinghai–Tibet railway from 2001 to 2006. Genotyping was performed using PCR-RFLP, PCR-SSCP and PCR-direct-sequencing techniques. Promoter activity was evaluated by luciferase reporter assays. Gene–gene interaction was conducted by MDR v.2.0, and haplotype–diplotype analysis by Haplo.stats v.1.4.0. Results Significant differences were observed in the genotype ( P = 0.0136) and allele ( P = 0.0299) distributions of rs1008438, and in rs1061581 allele distribution ( P = 0.0421) between HAPE patients and controls. Interaction analysis indicated that 3 polymorphisms (rs1061581, rs1043618 and rs1008438) shared strong synergism with a testing accuracy of 0.792 and cross-validation consistency 10 out of 10 ( P = 0.001). Haplotypes Hap4 (G–C–A, in order of rs1061581, rs1043618 and rs1008438) and Hap5 (G–G–A) had an 86% reduced risk ( P = 0.0009) against and Hap7 (A–C–C) had a 2.43-fold increased risk for HAPE. When considered as diplotypes, significance was noted for Dip5 (Hap1–Hap7) (OR = 3.39; 95% CI: 1.28–9.17; P = 0.0140). Functional assessment supported the involvement of rs1008438 in the pathogenesis of HAPE. Conclusion We demonstrated strong interaction of rs1061581, rs1043618 and rs1008438 polymorphisms within Hsp70 family upon susceptibility to HAPE in Chinese. Moreover, polymorphism rs1008438 might cause the development of HAPE via a change in HSPA1A promoter activity.

Effect of Altitude on the Heart and the Lungs

This review focuses on the effects of altitude exposure from 1 to several days or weeks as occurs in tourists, trekkers, and mountaineers who visit high altitude and normally reside near sea level. We briefly review the acute physiological adjustments and early acclimatization that occur in the cardiovascular system and the lungs of healthy individuals. These ensure life-sustaining oxygen delivery to the tissues despite a reduction in the partial pressure of inspired oxygen between 20% and 60% at 2500 and 8000 m, respectively. One of the acute adjustments, hypoxic pulmonary vasoconstriction (HPV), may be disadvantageous in those with a vigorous response and lead to 2 potentially lethal illnesses, high-altitude pulmonary edema (HAPE) and subacute mountain sickness (SAMS), which we present in more detail. Finally, on the basis of knowledge about the acute physiological adjustments and acclimatization and, when available, a review of the literature, we discuss the high-altitude tolerance of patients with coronary artery disease, congestive heart failure, arrhythmias, systemic hypertension, and pulmonary hypertension. ### Circulation The major effects of acute hypoxia on the heart and lung are shown in Figure 1. Hypoxia directly affects the vascular tone of the pulmonary and systemic resistance vessels and increases ventilation and sympathetic activity via stimulation of the peripheral chemoreceptors.1 Interactions occur between the direct effects of hypoxia on blood vessels and the chemoreceptor-mediated responses in the systemic and pulmonary circulation. Figure 1. Effects of hypoxia on systemic and pulmonary circulation. Unraveling the underlying mechanisms of the hypoxic vasodilatation of systemic arterioles is an active area of research. Several mechanisms appear to regulate local oxygen delivery according to the needs of the tissues2,3; for instance, the release of ATP from red blood cells and the generation of NO by various ways appear to regulate local oxygen delivery according to the needs …

Hypoxia has a greater effect than exercise on the redistribution of pulmonary blood flow in swine

Strenuous exercise combined with hypoxia is implicated in the development of high-altitude pulmonary edema (HAPE), which is believed to result from rupture of pulmonary capillaries secondary to high vascular pressures. The relative importance of hypoxia and exercise in altering the distribution of pulmonary blood flow (PBF) is unknown. Six chronically catheterized specific pathogen-free Yorkshire hybrid pigs (25.5 +/- 0.7 kg, means +/- SD) underwent incremental treadmill exercise tests in normoxia (Fi(O(2)) = 0.21) and hypoxia (Fi(O(2)) = 0.125, balanced order), consisting of 5 min at 30, 60, and 90% of the previously determined Vo(2max). At steady state (~4 min), metabolic and cardiac output data were collected and fluorescent microspheres were injected over approximately 30 s. Later the fluorescent intensity of each color in each 2-cm(3) lung piece was determined and regional perfusion was calculated from the weight-normalized fluorescence. Both hypoxia and exercise shifted PBF away from the ventral cranial lung regions toward the dorsal caudal regions of the lung, but hypoxia caused a greater dorsal caudal shift in PBF at rest than did near-maximal exercise in normoxia. The variance in PBF due to hypoxia, exercise, and vascular structure was 16 +/- 4.2, 4.0 +/- 4.4, and 59.4 +/- 11.4%, respectively, and the interaction between hypoxia and exercise represented 12 +/- 6.5%. This observation implies that there is already a maximal shift with in PBF with hypoxia in the dorsal-caudal regions in pigs that cannot be exceeded with the addition of exercise. However, exercise greatly increases the pulmonary arterial pressures and therefore the risk of capillary rupture in high flow regions.