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PATHOPHYSIOLOGICAL ANALYSIS OF BRONCHIOLITIS OBLITERANCE USING CD40-DEFICIENT MICE

使用 CD40 缺陷小鼠对细支气管炎闭塞的病理生理学分析

基本信息

批准号：
13670596
负责人：
HASEGAWA Yoshinori
金额：
$ 2.18万
依托单位：
NAGOYA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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

项目摘要

Cases of constrictive bronchiolitis obliterans (BO) have been reported involving patients with bone marrow transplants and heart/lung transplants as well as those with rheumatoid arthritis with or without penicillamine treatment. Although constrictive BO was a relatively rare disease, it has recently become the focus of renewed interest because the number of allograft recipients such as bone marrow and heart/lung transplants has been increasing. To investigate the pathogenesis of BO, we focused on the establishment of mouse experimental mode for BO and the role of CD40 molecule. When wild-type (WT) mice and CD40KO mice were injected intratracheally with LPS, LPS-induced lung injury was significantly reduced in CD40KO mice. Further, LPS-induced inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production was also inhibited in the lungs of CD40KO mice. In addition, the release of inflammatory mediators, that is, TNF-α, IL-1β, macrophage inflammatory protein 2 (MIP-2), reactive oxygen, nitrogen intermediates and MMP-9 into the bronchoalveolar lavage fluid, was significantly reduced in CD40KO mice. We studied the function of alveolar macrophages (AMφ) in each of mice ex vivo. Although iNOS in WT AMφ was induced in response to LPS, no iNOS expression could be detected in CD40KO AMφ. These results indicated that an absence of CD40 signaling followed by the decrease of the production of inflammatory mediators attenuated lung injury in uarine model. Our data suggest that the functional blockade of CD40 would yield one of the targets for the clinical treatment for lung injury including BO.

据报道，缩窄性闭塞性细支气管炎 (BO) 病例涉及骨髓移植和心/肺移植患者以及接受或不接受青霉胺治疗的类风湿性关节炎患者。尽管缩窄性BO是一种相对罕见的疾病，但由于骨髓和心/肺移植等同种异体移植受者的数量不断增加，它最近重新成为人们关注的焦点。为了探讨BO的发病机制，我们重点关注BO小鼠实验模式的建立以及CD40分子的作用。当野生型（WT）小鼠和CD40KO小鼠气管内注射LPS时，LPS诱导的CD40KO小鼠肺损伤显着减轻。此外，CD40KO 小鼠肺中 LPS 诱导的诱导型一氧化氮合酶 (iNOS) 表达和一氧化氮 (NO) 产生也受到抑制。此外，CD40KO小鼠支气管肺泡灌洗液中炎症介质，即TNF-α、IL-1β、巨噬细胞炎症蛋白2（MIP-2）、活性氧、氮中间体和MMP-9的释放显着减少。我们离体研究了每只小鼠的肺泡巨噬细胞（AMφ）的功能。尽管WT AMφ中的iNOS是响应LPS而诱导的，但在CD40KO AMφ中未检测到iNOS表达。这些结果表明，CD40 信号传导的缺失以及炎症介质产生的减少减轻了尿液模型中的肺损伤。我们的数据表明，CD40 的功能性阻断将成为包括 BO 在内的肺损伤临床治疗的靶标之一。