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.
ABSTRACT
Background and objective: Based on the reported biological properties and function of vascular endothelial growth factor (VEGF) in hypoxic conditions, many investigations have studied the ...hypothesis that VEGF has an important role in the pathogenesis of high altitude sicknesses, including high‐altitude pulmonary oedema (HAPE). Unfortunately, the results are inconsistent. Therefore, the association of VEGF gene single nucleotide polymorphisms (SNP) with being susceptible to HAPE was investigated.
Methods: The study included 53 HAPE‐susceptible subjects (HAPE‐s) and 69 HAPE‐resistant mountaineer controls (HAPE‐r). Subjects were Japanese and the two groups were comparable in terms of age and gender. The SNP of the VEGF gene, namely C‐2578A, G‐1154A and T‐460C in the promoter, G + 405C in the 5′‐untranslated region and C936T in the 3′‐untranslated region, were examined by allele discrimination experiments. In addition, arterial oxygen tension (PaO2) and pulmonary haemodynamic data were available for 21 of the HAPE‐s subjects.
Results: There were no statistically significant differences in the allele frequencies, genotype distributions or haplotype frequencies of VEGF SNP between the HAPE‐s and HAPE‐r groups. Furthermore, neither PaO2 nor pulmonary haemodynamic parameters were associated with the VEGF SNP in the 21 HAPE‐s subjects.
Conclusions: This genetic study did not provide evidence that functional SNP of the VEGF gene are associated with susceptibility to HAPE in a Japanese population.
Pulmonary hypertension is a hallmark of high-altitude pulmonary oedema (HAPE) and of congestive right heart failure in subacute mountain sickness (SMS) and chronic mountain sickness (CMS) in the ...Himalayas and in the end-stage of CMS (Monge's disease) in the Andes. There are studies to suggest that transmission of excessively elevated pulmonary artery pressure and/or flow to the pulmonary capillaries leading to alveolar haemorrhage is the pathophysiological mechanism of HAPE. In the Himalayas, HAPE was successfully prevented by extending the acclimatisation period from a few days to 5 weeks, however, this did not prevent the occurrence of congestive right heart failure after several weeks of stay at 6,000 m. This leads to the concept that rapid remodelling of the small precapillary arteries prevents HAPE but not the development of right heart failure in SMS and CMS. Unresponsiveness of pulmonary hypertension to oxygen at high altitude and its complete resolution only after weeks of stay at low altitude suggest that structural rather than functional changes are its pathophysiological mechanism. Since pulmonary hypertension at high altitude is the driving force leading to high-altitude pulmonary oedema and "high-altitude right heart failure" in newcomers and residents of high altitude, the authors propose to adjust current terminology accordingly.
The response of pulmonary artery pressure to high altitude has not been studied in children. It is also not known whether the individual response is hereditary. Therefore, the response of pulmonary ...artery pressure to high altitude was measured in pre-pubertal children in comparison to that in their biological fathers. Echocardiography was performed at 450 m and over 3 days at 3,450 m. Systolic pulmonary artery pressure was estimated from the pressure gradient of tricuspid regurgitation. The increase in pulmonary artery pressure in children was greater than that in adults at day 1 of high altitude (15.5+/-9.1 versus 7.9+/-6.4 mmHg), but returned to adult levels on day 2. The increase in pulmonary artery pressure from low to high altitude of each child correlated with that in the father. Pre-pubertal children transiently develop greater pulmonary hypertension than their fathers when exposed to high altitude. The individual response of pulmonary pressure to high altitude seems to be at least partly hereditary.
The genes of the renin—angiotensin system (RAS) play an important role in the regulation of pulmonary vascular tone. Although studies on individual genes polymorphisms have reported association with ...high-altitude pulmonary oedema (HAPE), studies on multiple genes or epistasis are lacking. We therefore investigated the association of the RAS polymorphisms with HAPE. In a case-control design, we screened 163 HAPE-resistant/controls (HAPE-r) and 160 HAPEpatients (HAPE-p) of Indian origin for eight polymorphisms of four RAS genes, ACE, AGT, AGTR1 and AGTR2. Significant difference in genotype and allele frequencies of the ACE I/D and AGT M235T polymorphisms was observed between HAPE-p and HAPE-r (p < 0.05). In three-locus haplotype analysis of AGT the haplotype GTM was significantly higher in HAPE-p (29%) and haplotype GTT in HAPE-r (27%) after Bonferroni correction (p < 0.006). The differences were insignificant for polymorphisms from AGTR1 and AGTR2. The MDR (multifactor dimensional reduction) approach for gene—gene interaction depicted individual polymorphism M235T as the best disease predicting model (cross validation consistency, CVC = 10/10). We found a significant association of D allele of ACE and M allele of AGT with HAPE. The findings are supported at the haplotypic level as well as through nested genetic interaction between the RAS gene polymorphisms using the MDR approach.
Background and objective: High-altitude pulmonary oedema (HAPE) is a non-cardiogenic hydrostatic oedema involving a genetic component. Considering the low incidence of HAPE, sample sizes in current ...reports are relatively limited. We aimed to assess the association between the angiotensin-converting enzyme (ACE) I/D polymorphism and HAPE via a meta-analysis of published and unpublished data.
Materials and methods: We searched PubMed, CBM, CNKI, and Cochrane Library Database before 20 November 2010. A random-effects model was applied (STATA) and study quality was assessed in duplicate.
Results: A total of five studies including 305 cases and 662 controls were meta-analysed. The summary odds ratio (OR) indicated that no significant differences in risk of developing HAPE were found between carriers of ACE D and I alleles (OR = 1.20; 95% confidence interval (CI), 0.98–1.48; p = 0.084). Lack of association persisted for genotypes under the recessive mode. However, genotype association under the dominant mode showed D allele carriers significantly conferred a 1.55-fold increased HAPE risk compared with II genotype carriers (95% CI, 1.15–2.08; p = 0.004). Funnel plot and Egger’s test suggested no evidence of publication bias.
Conclusions: Our results supported the notion that ACE D allele carriers were at significant increased risk of developing HAPE.
High-altitude pulmonary oedema (HAPE) is a potentially fatal condition affecting fit and previously well individuals at altitudes in excess of 3000 m. This article discusses the mechanisms of HAPE, ...considers the contribution of hypoxic pulmonary vasoconstriction and alterations in sodium transport to the pathological process. It discusses the various biochemical mediators such as nitric oxide (NO), endothelin-1 (ET-1), and the renin-angiotensin-aldosterone system (RAS) that may be involved and considers possible oxygen-sensing mechanisms involved in hypoxic adaptation such as hypoxia-inducible factor-1 (HIF-1). Those who have had HAPE once run an unpredictable but significant risk of recurrence; therefore, there may be a constitutional or genetic component in its aetiology. This paper considers the possible involvement of genes that may be involved in physiological adaptation to hypoxia (e.g., angiotensin-1 AT(1)-converting enzyme ACE, tyrosine hydroxylase, serotonin transporter 5-HTT, and endothelial NO synthase eNOS genes). As yet, no formal association has been identified between an identified genetic polymorphism and HAPE, but genetic variation provides a possible mechanism to explain interindividual variation in response to hypoxia and enhanced or reduced performance at altitude.
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