PATHOPHYSIOLOGICAL MECHANISM AND GENETIC SUSCEPTIBILITY IN HIGH-ALTITUDE ACCLIMATIZATION

高海拔适应的病理生理机制和遗传易感性

• 批准号: 14570547
• 负责人: HANAOKA Masayuki
• 金额: $ 1.86万
• 依托单位: SHINSHU UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570547/
• 关键词: High-altitude pulmonary edema; Vascular endothelial growth factor; Bronchoalveolar lavage; Genetic polymorphism; Endothelial nitric oxide synthase; Tyrosine hydroxylase; Coagulation factor V; Angiotensin-converting enzyme; 健常登山家; 気管支肺胞洗浄; 免疫染色 /

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

1.血管内皮生长因子（VEGF）在高原肺水肿（HAPE）患者中过表达。已知肺中VEGF的增加诱导肺血管通透性增加，导致肺水肿。此外，已显示VEGF在缺氧条件下显著上调。为了研究VEGF在RAPE发病机制中的作用，我们检测了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BALF中VEGF的浓度明显降低，表明患者肺中VEGF的产生受到抑制。2.基因多态性与高原肺水肿易感者（HAPE-s）的病例对照关联研究1）内皮素受体（VEGF）基因多态性与肺水肿易感者（HAPE-s）基因多态性的关系1）内皮素受体（VEGF）基因多态性与肺水肿易感者（HAPE-s）基因多态性的关系2）内皮素受体（VEGF）基因多态性与肺水肿易感者（HAPE-s）基因多态性的关系3）内皮素受体（VEGF）基因多态性与肺水肿易感者（HAPE-s）基因多态性的关系 ...更多信息 一氧化氮合酶（eNOS）基因肺中一氧化氮（NO）合成的缺陷被认为有助于增强HAPE-s中的缺氧性肺血管收缩。我们研究了两个多态性的eNOS基因，Glu 298 Asp变体和27个碱基对（bp）可变数目的串联重复序列（VNTR），在HAPE-S和健康的登山者控制在日本人口。我们发现eNOS基因Glu 298 Asp变异和27-bp VNTR多态性与HAPE-s有显著正相关。酪氨酸羟化酶（TH）基因HAPE-s组的缺氧通气反应（HVR）减弱，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。我们检测了具有（TCAT）_n四核苷酸微卫星重复序列和TH基因中Met 81 Val变异的HAPE-s的钝端HVR表型。（TCAT）_n四核苷酸重复序列和TH基因Met 81 Va 1变异多态性在HAPE组和对照组间均无显著性相关。3）血管紧张素转换酶（ACE）基因ACE在肺动脉高压的发病中起重要作用，提示ACE在HAPE的发生发展中起关键作用。应用聚合酶链反应（PCR）技术检测ACE基因插入/缺失（I/D）多态性（ACE-I/D）。ACE-I/D基因多态性在HAPE组和对照组之间的分布差异无统计学意义。D阳性HAPE患者入院时肺血管阻力及其指数明显高于I阳性HAPE患者。少

项目成果

Droma Y, et al.: "The R^<506>Q mutation of coagulation factor V gene in high-altitude pulmonary edema susceptible subjects"High Altitude Medicine & Biology. 4. 497-498 (2003)

Droma Y等：“高原肺水肿易感人群凝血因子V基因R^<506>Q突变”高原医学

Hotta J, et al.: "Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects"Chest. (in press).

Hotta J 等人：“日本受试者中肾素-血管紧张素系统基因的多态性与高原肺水肿的关系”胸部。

Hanaoka M, et al.: "Vascular endothelial growth factor in patients with high-altitude pulmonary edema."J Appl Physiol. 94. 1836-1840 (2003)

Hanaoka M 等人：“高原肺水肿患者的血管内皮生长因子。”J Appl Physiol。

Droma Y, et al.: "The R^<506>Q mutation of coagulation factor V gene in high-altitude pulmonary edema susceptible subjects."High Alt Med Biol. 4. 497-498 (2003)

Droma Y 等人：“高原肺水肿易感受试者中凝血因子 V 基因的 R^<506>Q 突变。”High Alt Med Biol。

花岡正幸 ほか: "呼吸器疾患関連遺伝子異常-肺循環に関する遺伝子異常-"分子呼吸器病. 7. 55-58 (2003)

Masayuki Hanaoka 等人：“呼吸系统疾病相关的遗传异常 - 与肺循环相关的遗传异常”《分子呼吸疾病》。