PATHOPHYSIOLOGICAL ANALYSIS OF BRONCHIOLITIS OBLITERANCE USING CD40-DEFICIENT MICE

据报道，缩窄性闭塞性毛细支气管炎(BO)患者涉及骨髓移植和心肺移植，以及使用或不使用青霉胺治疗的类风湿性关节炎患者。虽然缩窄性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的数量不断增加，它最近已成为人们重新关注的焦点。为了探讨BO的发病机制，我们重点建立了BO的小鼠实验模型，并探讨了CD40分子的作用。给野生型(WT)和CD40KO小鼠气管内注射内毒素后，CD40KO小鼠的肺损伤明显减轻。此外，内毒素诱导的诱导型一氧化氮合酶(INOS)表达和一氧化氮(NO)在CD40KO小鼠肺中的表达也受到抑制。此外，CD40KO小鼠肺泡灌洗液中的炎症介质，即肿瘤坏死因子-α、白介素1-β、巨噬细胞炎性蛋白-2、活性氧、氮中间体和基质金属蛋白酶-9的释放明显减少。我们在体外研究了小鼠肺泡巨噬细胞(AM-φ)的功能。内毒素诱导WT AMφ诱导型一氧化氮合酶表达，而CD40KO AMφ未检测到诱导型一氧化氮合酶表达。这些结果表明，CD40信号的缺失和炎性介质的产生减少减轻了Uarine模型的肺损伤。我们的数据表明，CD40的功能阻断将成为包括BO在内的肺损伤临床治疗的靶点之一。

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.