PATHOPHYSIOLOGICAL MECHANISM AND GENETIC SUSCEPTIBILITY IN HIGH-ALTITUDE ACCLIMATIZATION

1.血管内皮生长因子（VEGF）在高原肺水肿（HAPE）患者中的过表达。已知肺中VEGF的增加会导致肺血管通透性增加，导致肺水肿。此外，VEGF已被证明在缺氧条件下明显上调。为了研究VEGF在血管内皮生长因子（HAPE）发病机制中的作用，我们测量了HAPE患者和健康志愿者静脉血清和支气管肺泡灌洗液（BALF）中VEGF的浓度。与对照组相比，患者肺BALF中VEGF的浓度明显下降，说明患者肺中VEGF的生成受到了干扰。此外，患者BALF中VEGF的剥夺逐渐改善，恢复期静脉血清中VEGF的动态类似。高海拔肺水肿易感者（HAPE-s）基因多态性的病例-对照研究1)内皮型一氧化氮合酶（eNOS）基因缺陷被认为是HAPE-s缺氧性肺血管收缩增强的原因之一。我们在日本人群的HAPE-s和健康攀援对照中检测了eNOS基因的两种多态性，Glu298Asp变体和27个碱基对（bp）可变数串联重复序列（VNTR）。我们发现，Glu298Asp变异和eNOS基因的27bp VNTR多态性与HAPE-s呈显著正相关。同时具有两个显著等位基因的携带者仅存在于HAPE-s组。2)在HAPE-s中观察到酪氨酸羟化酶（Tyrosine hydroxylase， TH）基因减弱的缺氧通气反应（HVR）， TH是颈动脉体对缺氧反应合成多巴胺神经递质以增强通气的限速酶。我们用（TCAT）_n四核苷酸微卫星重复序列和TH基因的Met81Val变异检测了HAPE-s钝化HVR的表型。在（TCAT）_n四核苷酸重复序列或TH基因Met81Va1变异多态性方面，HAPE-s与对照之间均未发现显著相关性。3)血管紧张素转换酶（Angiotensin-converting enzyme， ACE）基因在肺动脉高压的发病机制中起重要作用，被认为在HAPE的发展过程中起关键作用。应用聚合酶链反应研究ACE基因的插入/缺失（I/D）多态性。ACE-I/D多态性在HAPE-s组与对照组之间的分布无显著差异。而肺血管阻力及入院时肺血管阻力指数在D阳性组明显高于I阳性组。少

1.Vascular endothelial growth factor (VEGF) in patients with high-altitude pulmonary edema (HAPE)Overexpression. of VEGF in the lung is known to induce an increased pulmonary vascular permeability resulting in pulmonary edema. Furthermore, VEGF has been shown to be markedly up-regulated in the hypoxic condition. To examine the role of VEGF in the pathogenesis of RAPE, we measured the concentrations of VEGF in venous serum and bronchoalveolar lavage fluid (BALF) in patients with HAPE and healthy volunteers. The concentration of VEGF in the BALF of patients was markedly deprived compared with that in controls, indicating the production of VEGF is insulted in the lung of the patients. In addition, the deprived VEGF in the BALF of the patients was improved gradually, following a similar VEGF dynamics in venous serum during the stage of recovery.2.Case-control association studies about the genetic polymorphisms with high-altitude pulmonary edema susceptible subjects (HAPE-s)1)Endothelial ni … More tric oxide synthase (eNOS) geneA defect in nitric oxide (NO) synthesis in the lung is considered to contribute to enhance the hypoxic pulmonary vasoconstriction in HAPE-s. We examined two polymorphisms of the eNOS gene, the Glu298Asp variant and 27-basepair (bp) variable numbers of tandem repeats (VNTR), in HAPE-s and healthy climber controls in a Japanese population. We found significant positive associations of the Glu298Asp variant and 27-bp VNTR polymorphism of the eNOS gene with HAPE-s. Moreover, the carriers who possessed simultaneously both of the two significant alleles only existed in HAPE-s group.2)Tyrosine hydroxylase (TH) geneA blunted hypoxic ventilatory response (HVR) was observed in HAPE-s and the TH is a rate-limiting enzyme in the carotid body responding to hypoxia to synthesize dopamine neurotransmitter to heighten ventilation. We examined the phenotype of the blunted HVR of HAPE-s with the (TCAT)_n tetranucleotide microsatellite repeats and the Met81Val variant in the TH gene. No significant association regarding either the (TCAT)_n tetranucleotide repeats or the Met81Va1 variant polymorphism of the TH gene was found between HAPE-s and controls.3)Angiotensin-converting enzyme (ACE) geneACE plays an important role in the pathogenesis of pulmonary hypertension that is suggested to be critical in the development of HAPE. The Insertion/Deletion (I/D) polymorphism in ACE gene (ACE-I/D) was investigated by polymerase chain reaction. There was no significant difference of the distribution of the ACE-I/D polymorphism between the HAPE-s and control groups. However, pulmonary vascular resistance and its index on admission were significantly higher in the HAPE-s with D positivity than in the HAPE-s with I positivity. Less