PATHOPHYSIOLOGICAL MECHANISM AND INDIVIDUAL SUSCEPTIBILITY IN HIGH-ALTITUDE ILLNESS

高原病的病理生理机制和个体易感性

• 批准号: 13470126
• 负责人: KUBO Keishi
• 金额: $ 4.61万
• 依托单位: SHINSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470126/
• 关键词: High-altitude pulmonary edema; Pathology; Immunohistochemical staining; Vascular endothelial growth factor; Bronchoalveolar lavage; Genetic polymorphism; Endothelial nitric oxide synthase; Tyrosine hvdroxylase; 一酸化窒素; 肺高血圧; 低酸素換気応答; 頚動脈体; 高知肺水

A. Further pathological study on high-altitude pulmonary edema by autopsied casesWe performed hematoxylin and eosin staining in lung materials obtained from 4 autopsied cases in Japan. The findings were the diffuse alveolar edema infiltrating with red blood cells, polymorphonuclear cells and macrophages; the congestion of alveolar capillaries and pulmonary arterioles; and the multi-thrombi and fibrin clots plugging in the congested small vessels. We also undertook the immunohistochemical staining for type II pneumocytes, pulmonary surfactant (PS) and mast cells in the lung tissue from one autopsied case to examine the biological changes within the lung parenchyma. We found that the type II pneumocytes showed cellular fusion, deformity and exfoliation from the walls of alveoli; the PS was patchily distributing within the lung parenchyma and the mast cells were increased and clustered around the pulmonary small vessels.B. Vascular endothelial growth factor (VEGF) in patients with high-al … More titudepulmonary edemaWe measured the concentration of VEGF in bronchoalveolar lavage fluid (BALF) and venous serum in patients with HAPE at the points of admission and discharge, respectively. The noteworthy finding in this study was that the VEGF in BALF of patients was markedly deprived at admission and that the immunohistochemicalexamination showed a negative staining of VEGF in the lung of HAPE. Furthermore, the deprived VEGF in BALF of the patients was improved gradually, following a similar VEGF dynamics in venous serum during the stage of recovery.C. Case-control association studies about the genetic polymorphisms with high-altitude pulmonary edema susceptible subjects (HAPE-s)A 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 endothelial NO synthase (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.Another association study was about the phenotype of the blunted hypoxic ventilatory response (HVR) of HAPE-s with the (TCAT)_n tetranucleotide microsatellite repeats and the Met81Val variant in the tyrosine hydroxylase (TH) gene. This study was designed because a blunted 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. However, no significant association regarding either the (TCAT)_n tetranucleotide repeats or the Met81Val variant polymorphism of the TH gene was found between HAPE-s and controls. Less

A.高原肺水肿的进一步病理研究我们对日本4例尸检病例的肺组织进行苏木精和伊红染色。表现为弥漫性肺泡水肿，红细胞、多形核细胞和巨噬细胞浸润；肺泡毛细血管和肺小动脉充血；多血栓和纤维蛋白凝块堵塞了充血的小血管。我们还对1例尸检患者肺组织中的II型肺细胞、肺表面活性物质（PS）和肥大细胞进行免疫组化染色，观察肺实质内的生物学变化。我们发现II型肺细胞表现为细胞融合、畸形和肺泡壁脱落；肺实质内呈斑片状分布，肥大细胞增多，聚集在肺小血管周围。血管内皮生长因子（VEGF）在高强度肺水肿患者中的含量我们分别测定了HAPE患者入院和出院时支气管肺泡灌洗液（BALF）和静脉血清中VEGF的浓度。本研究中值得注意的发现是患者入院时BALF中VEGF明显缺失，免疫组化检查显示HAPE肺中VEGF呈阴性染色。此外，患者BALF中被剥夺的VEGF逐渐改善，与恢复阶段静脉血清中VEGF的动态相似。高原肺水肿易感者（HAPE-s）基因多态性的病例-对照相关性研究认为，肺一氧化氮（NO）合成缺陷可促进HAPE-s缺氧性肺血管收缩。我们检测了内皮NO合成酶（eNOS）基因的两种多态性：Glu298Asp变异和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。另一项关于HAPE-s迟钝缺氧通气反应（HVR）表型与酪氨酸羟化酶（TH）基因（TCAT）_n四核苷酸微卫星重复序列和Met81Val变异的关联研究。本研究的设计是因为在HAPE-s中观察到钝化的HVR，并且TH是颈动脉体中的限速酶，响应缺氧合成多巴胺神经递质以增强通气。然而，在（TCAT）_n四核苷酸重复或TH基因的Met81Val变异多态性方面，HAPE-s与对照之间没有发现显著的关联。少

项目成果

Hanaoka M., et al.: "Vascular endothelial growth factor in patients with high-altitude pulmonary edema."J Appl Physiol. in press

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

Hanaoka M, et al.: "Vascular endothelial growth factor in patients with high-altitude pulmonary edema"Journal of Applied Physiology. Jan.10. (2003)

Hanaoka M等人：“高原肺水肿患者的血管内皮生长因子”应用生理学杂志。

Droma Y, et al.: "Pathological features of the lung in fatal high altitude pulmonary edema occurring at moderate altitude in Japan"High Altitude Medicine & Biology. 2・4. 515-523 (2001)

Droma Y 等：“日本中海拔地区致命性高原肺水肿的肺部病理特征”《高原医学与生物学》2·4（2001 年）。

Droma Y., et al.: "Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema"Circulation. 106. 826-830 (2002)

Droma Y. 等人：“内皮型一氧化氮合酶基因多态性与高原肺水肿的正相关”循环。

Hanaoka M., et al.: "Polymorphisms of the tyrosine hydroxylase gene in subjects susceptible to high-altitude pulmonary edema"Chest. 123. 54-58 (2003)

Hanaoka M.等人：“易患高原肺水肿的受试者中酪氨酸羟化酶基因的多态性”胸部。