PATHOPHYSIOLOGICAL ANALYSIS OF BRONCHIOLITIS OBLITERANCE USING CD40-DEFICIENT MICE

缩窄性闭塞性细支气管炎（BO）的病例有报道，涉及骨髓移植和心肺移植患者以及类风湿关节炎患者，治疗或不治疗青霉胺。虽然缩窄性BO是一种相对罕见的疾病，但由于骨髓和心脏/肺移植等同种异体移植受体的数量不断增加，它最近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的小鼠实验模型和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小鼠肺损伤明显减轻。此外，lps诱导的诱导型一氧化氮合酶（iNOS）的表达和一氧化氮（NO）的产生也在CD40KO小鼠肺中受到抑制。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的释放明显减少。我们研究了肺泡巨噬细胞（AMφ）在小鼠体内的功能。LPS可诱导WT AMφ中iNOS的表达，而CD40KO AMφ中未检测到iNOS的表达。这些结果表明，CD40信号缺失后炎症介质产生的减少减轻了小鼠模型的肺损伤。我们的数据表明，CD40的功能性阻断将成为临床治疗肺损伤（包括BO）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.