Endothelin-1 receptor antagonists prevent the development of pulmonary emphysema in rats.

We hypothesised that endothelin (ET)-1 plays an important role in the pathogenesis of emphysema. We attempted to apply ET-1 receptor antagonists to demonstrate and further elucidate the molecular pathogenesis pathways through which ET-1 may cause emphysematous changes. Sprague-Dawley rats were divided into four groups: control, cigarette smoke extract (CSE), CSE+BQ-123 (a selective endothelin receptor type A (ET(A)) antagonist) and CSE+bosentan (a mixed ET(A)/ET(B) receptor antagonist). The CSE was injected intraperitoneally once a week for 3 weeks, and BQ-123 or bosentan was administered daily for the same duration. The expression of ET(A) receptor, apoptosis index, caspase-3 activity, matrix metalloproteinase (MMP)-2 and MMP-9 activity, and tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations were measured in the lung tissue. The ET-1 levels and antioxidant activity were measured in the serum. Both BQ-123 and bosentan prevented the development of CSE-induced emphysema, blocked the expression of ET(A) receptor, inhibited pulmonary apoptosis, inactivated MMP-2 and MMP-9 activities in the lung tissues, reduced the concentrations of inflammatory cytokines TNF-alpha and IL-1beta, and improved the biological antioxidant activity in the serum. Emphysema development is suppressed by ET-1 receptor antagonists. ET-1 may cause emphysematous changes through molecular pathogenesis pathways involving apoptosis, proteinase and antiproteinase imbalance, inflammation and oxidative stress.

Hypoxia-induced pulmonary blood redistribution in subjects with a history of high-altitude pulmonary edema.

BACKGROUND: Pulmonary hypertension has been suggested to play an important role in development of high-altitude pulmonary edema (HAPE), and individual susceptibility has been suggested to be associated with enhanced pulmonary vascular response to hypoxia. We hypothesized that much greater pulmonary vasoconstriction would be induced by acute alveolar hypoxia in HAPE-susceptible (HAPE-s) subjects and that changes in pulmonary blood flow distribution could be demonstrated by radionuclide study. METHODS AND RESULTS: We performed ventilation-perfusion scintigraphy in 8 HAPE-s subjects and 5 control subjects while each was in the supine position and acquired functional images of pulmonary blood flow and ventilation under separate normoxic and hypoxic (arterial oxygen saturation, 70%) conditions. We also measured acceleration time/right ventricular ejection time (AcT/RVET) with Doppler echocardiography under each condition in both groups. Moreover, we assayed human leukocyte antigen (HLA) alleles serologically in the HAPE-s group. Pulmonary blood flow was significantly shifted from the basal lung region to the apical lung region under hypoxia in HAPE-s subjects, although no significant change in regional ventilation was observed. With Doppler echocardiography, HAPE-s subjects showed increased pulmonary arterial pressure during hypoxia compared with control subjects. The magnitude of cephalad redistribution of lung blood flow was significantly higher in the HLA-DR6-positive than in HLA-DR6-negative HAPE-s subjects. CONCLUSIONS: These findings suggest that acute hypoxia induces much greater cephalad redistribution of pulmonary blood flow that results from exaggerated vasoconstriction in the basal lung in HAPE-s subjects. Furthermore, pulmonary vascular hyperreactivity to hypoxia may be associated with HLA-DR6.

Pathological features of the lung in fatal high altitude pulmonary edema occurring at moderate altitude in Japan.

In order to characterize the pathological features of high altitude pulmonary edema (HAPE) occurring at moderate altitude in Japan, we performed routine hematoxylin and eosin (HE) staining in lung materials from HAPE autopsied cases. We also undertook advanced immunohistochemical staining for observation of type II pneumocytes, pulmonary surfactant (PS), and mast cells in the lung of HAPE cases to examine the biological changes within the lung parenchyma. The pathological findings of HAPE were characterized by alveolar edema, congestion of pulmonary vessels, alveolar hyaline membranes, alveolar hemorrhage, and multithrombi and fibrin clots, but maintained alveolar structure. The immunostaining results showed that the type II pneumocytes were cellular fusion, deformity, and exfoliation from the walls of alveoli; the PS not only lined the alveolar surface, but was also patchily distributed within alveoli; and the number of mast cells were increased (9.0 +/- 0.9 cells/mm(2)) compared to that in controls (1.1 +/- 0.4 cells/mm(2)) (p < 0.01). We conclude that the pathological features of HAPE at moderate altitude in Japan are similar to others reported worldwide, and that the type II pneumocytes, PS, and mast cells may contribute to some extent to pathophysiological parts in the development and progression of HAPE.

Acute hypoxic pulmonary vascular response does not accompany plasma endothelin-1 elevation in subjects susceptible to high altitude pulmonary edema.

We have previously shown that high altitude pulmonary edema-susceptible subjects (HAPE-S) have an accentuated pulmonary vascular response to hypoxia. In this study, we investigated the relationship between plasma endothelin-1 (ET-1) levels and the acute hypoxic pulmonary vascular response in HAPE-S and control subjects. In six HAPE-S and seven healthy subjects, we evaluated acceleration time/right ventricular ejection time (AcT/RVET) using Doppler echocardiography, and measured plasma ET-1 levels by radioimmunoassay (RIA) before and after 5 minutes of breathing 10% oxygen. The HAPE-S showed a significantly increased pulmonary vascular response to hypoxia compared with healthy subjects. However, no statistically significant changes of plasma ET-1 levels were observed before and after hypoxia in both groups. We conclude that the increased pulmonary vascular response to acute hypoxia in HAPE-S may not be related to ET-1 release.

Association between human polymorphic DNA markers and hypoxia adaptation in Sherpa detected by a preliminary genome scan.

Genetic determinants of resistance to hypobaric hypoxia in the Sherpa are still unknown. Since adaptive gene variants must still be subjected to positive selection, linkage disequilibrium between such variants and specific alleles of flanking DNA markers is expected. Following this line of reasoning, we performed a human genome scan using 998 polymorphic DNA markers in 7 unrelated Sherpa porters living in the Solu-Khumbu area. This minimalist approach succeeded in detecting 8 DNA markers showing homozygosity for the same shared allele. Analysis of additional DNA samples from 2 more Sherpa porters focused our attention on three polymorphic DNA markers (D6S1697, D14S274, D17S1795) showing homozygosity for the same shared allele in 8 out 9 tested individuals. Analysis of DNA samples from Sherpa and non-Sherpa populations of Nepal proved HW equilibrium in both populations for markers D14S274 and D17S1795, while an excess of heterozygotes was observed in the Sherpa population for marker D6S1697. A significant difference in allele frequencies for D14S274 and D17S1795 between the two populations was observed. These findings exclude the possibility that homozygosity for 3 specific loci in 8 unrelated individuals might be ascribed to inbreeding or recent genetic drift. We therefore conclude that the chromosomal segments detected by such DNA markers may include genes involved in adaptation to hypobaric hypoxia.

Prevalence and severity of asthma and allergies in schoolchildren in Lhasa, Tibet.

BACKGROUND: The International Study of Asthma and Allergies in Childhood (ISAAC) demonstrated that large variations existed in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis and eczema throughout the world and that environmental factors and lifestyle customs are major determinants of the prevalence and severity of these diseases. However, the relevant data about children living at high-altitude locations were considered to be underreported. OBJECTIVE: The ISAAC Phase III programme was carried out in Lhasa, the Tibetan Autonomous Region in China, at an elevation of 3658 m above sea level to examine the occurrence of asthma, allergic rhinoconjunctivitis and eczema in schoolchildren aged 13-14 years. METHODS: All 3196 schoolchildren in eight public junior high schools in urban Lhasa who were confirmed to be 13-14 years old were invited and participated in both written and video questionnaire investigations, among which 3190 pieces of data (49.8% of boys and 50.2% of girls) were validated and analysed. RESULTS: Among the overall observations, the prevalence of 'having ever experienced wheezing', 'current wheezing' and 'diagnosed to have asthma' was 1.4%, 0.8% and 1.1%, respectively. The prevalence of current exercise-induced asthma and current nocturnal cough was 7.1% and 4.6%, respectively. The current prevalence of allergic rhinoconjunctivitis and eczema was 5.2% and 0.4%, respectively. In addition, the prevalence of rhinoconjunctivitis symptoms during the past 12 months showed no discernable differences throughout the year. CONCLUSION: The prevalence of asthma, allergic rhinoconjunctivitis and eczema over the past 12 months was the lowest among the centres, that performed ISAAC worldwide.

Endothelin-1 and interleukin-8 in high altitude pulmonary oedema.

We present a case of high altitude pulmonary oedema (HAPE) with pulmonary hypertension and polymorphonuclear leucocyte (PMN) accumulation in bronchoalveolar lavage fluid (BALF), which occurred in a 21 year old man. Plasma endothelin-1 (ET-1) and interleukin-8 (IL-8) concentration in BALF were elevated on admission, and returned to normal level at recovery, when the pulmonary artery pressure and the PMN counts in BALF were normal. In addition, E-selectin and intercellular adhesion molecule-1 (ICAM-1) in BALF were also slightly increased on admission. These findings suggest that endothelin-1 is a vasoconstrictor which contributes to the pulmonary hypertension in high altitude pulmonary oedema, and that some of the inflammatory mediators play an important role in chemotaxis and accumulation of polymorphonuclear leucocytes in the development of high altitude pulmonary oedema.