Evaluations of Specific Endothelial Cell Markers in Lung Alveolar Capillaries

肺泡毛细血管特异性内皮细胞标志物的评估

• 批准号: 11470143
• 负责人: KAWANAMI Oichi
• 金额: $ 9.34万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470143/
• 关键词: alveolar capillary; vascular endothelial cell; protease-activated receptor; thrombomodulin; thrombin; lung adenocarcinoma; lung injury; serine protease; VEGF; KDR; Flt; laser capture microdissection; confocal laser scanning microscope; RT-PCR

Morphology of the alveolar capillaries in the lung has been well documented under healthy and pathologic conditions. However, so-far available results could be summarized as plain observations by light and electron microscopies, and the functional implication derived from them is far from satisfactory. In order to explain and evaluate phenotypic activation of alveolar capillary endothelial cells, our observation has been focusing on a single unit capillary of alveolar walls in the lung. Together with electron and confocal laser scanning microscopies, multiple probing antigens, including anticoagulant thrombomodulin (TM), coagulant von Willebrand factor (vWf), protease-activated receptors (PAR) and their ligand-serine proteases, have been applied on human and experimental animal lungs. Important and novel findings we have obtained were as follows : 1) alveolar capillary endothelium lacked a conventional expression of vWf, but fully covered by TM ; 2) immunohistochemical conversion, from TM- to vWf-dominant phenotype, underwent when alveolar walls were damaged or metastasized by neoplastic cells of primary lung adenocarcinoma ; 3) PAR in endothelial cells elicited by nearby neoplastic cells facilitated a loss of TM while vWf started to accumulate ; and 4) activation of PAR on endothelial cells by serine proteases such as thrombin lead to exert a variety of biological activities, including cell growth and collagen production in alveolar wall cells. Thus, alveolar capillary endothelial cells might at least partly be a primary stimulator for repairing alveolar damages. In this connection alveolar capillary endothelial cells would be deeply involved in promoting cellular network functions among the alveolar wall cells. Our research aims are forwarding further to evaluate basic functions of endothelial cells in collagen vascular disease-related lung fibrosis.

在健康和病理条件下，肺泡毛细血管的形态已经被很好地记录下来。然而，到目前为止，现有的结果可以概括为通过光学和电子显微镜进行的简单观察，由此得出的功能含义远远不能令人满意。为了解释和评估肺泡毛细血管内皮细胞的表型激活，我们的观察集中在肺泡壁的单个单位的毛细血管上。结合电子显微镜和激光共聚焦扫描显微镜，多种探测抗原，包括抗凝剂血栓调节蛋白(TM)、凝血剂血管性血友病因子(VWF)、蛋白酶激活受体(PAR)及其配体-丝氨酸蛋白酶，已经应用于人和实验动物的肺组织。我们获得的重要和新颖的发现如下：1)肺泡毛细血管内皮细胞缺乏VWF的常规表达，但被TM完全覆盖；2)当原发肺腺癌的肿瘤细胞破坏肺泡壁或转移时，发生了以TM为主的免疫组织化学转化；3)邻近肿瘤细胞诱导内皮细胞PAR促进TM的丢失，而VWF开始积累；以及4)凝血酶铅等丝氨酸蛋白酶激活内皮细胞上的PAR，从而发挥多种生物学活性，包括细胞生长和肺泡壁细胞胶原的产生。因此，肺泡毛细血管内皮细胞可能至少部分是修复肺泡损伤的主要刺激因子。在这方面，肺泡毛细血管内皮细胞将深入参与促进肺泡壁细胞之间的细胞网络功能。我们的研究目的是进一步评估血管内皮细胞在胶原血管疾病相关肺纤维化中的基本功能。

项目成果

Jin E, Fujiwara M, Nagashima M, Shimizu H, Ghazizadeh M, Pan X, Arai S, Ohaki Y, Gomibuchi M, Takemura T, Kawanami O: "Aerogenous spread of primary lung adenocarcinoma induces ultrastructural remodeling of the alveolar capillary endothelium."Hum. Pathol..

Jin E、Fujiwara M、Nagashima M、Shimizu H、Ghazizadeh M、Pan X、Arai S、Ohaki Y、Gomibuchi M、Takemura T、Kawanami O：“原发性肺腺癌的气源性扩散诱导肺泡毛细血管内皮的超微结构重塑。”

Kurihara Y, Ghazizadeh M, Bo H, Shimizu H, Kawanami O, et al.: "Genome-wide screening of laser capture microdissected gastric signet-ring cell carcinomas"J.Nippon Med.Sch.. (In press). (2002)

Kurihara Y、Ghazizadeh M、Bo H、Shimizu H、Kawanami O 等人：“激光捕获显微解剖胃印戒细胞癌的全基因组筛查”J.Nippon Med.Sch.（正在出版）。

Jin E, Fujiwara M, Ghazizadeh M, Takemura T, Kawanami O: "Protease-activated receptors participate alveolar capillary angiogenesis in lung adenocarcinoma"(submitted). (2002)

Jin E、Fujiwara M、Ghazizadeh M、Takemura T、Kawanami O：“蛋白酶激活受体参与肺腺癌中的肺泡毛细血管生成”（已提交）。

Kawanami O, Jin E, Ghazizadeh M, Fujiwara M, Jiang L, Ohaki Y, Gomibuchi M, Takemura T.: "Mosaic-like distribution of endothelial cell antigens in capillaries and juxtaalveolar microvessels in the normal human lung"Pathol. Int.. 50(2). 136-141 (2000)

Kawanami O、Jin E、Ghazizadeh M、Fujiwara M、Jiang L、Ohaki Y、Gomibuchi M、Takemura T.：“正常人肺毛细血管和近肺泡微血管中内皮细胞抗原的马赛克样分布”Pathol。

Kawanami O.,Jin E., et al: "Heterogeneous distribution of thrombomodulin and von Willebrand factor inendothelial cells in the human pulmonary microvessels."Nippon Med Sch. 67(2). 118-125 (2000)

Kawanami O.，Jin E.，等人：“人肺微血管内皮细胞中血栓调节蛋白和冯维勒布兰德因子的异质分布。”Nippon Med Sch。