PATHOPHYSIOLOGICAL ANALYSIS OF BRONCHIOLITIS OBLITERANCE USING CD40-DEFICIENT MICE AND GFP-TRANSGENIC 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的小鼠实验模型以及CD40分子与骨髓源性祖细胞的作用。在此基础上，我们进一步研究了雌雄同体蜥脚类动物诱导的BO。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TNF-α、IL-1b、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（AMf）在每只小鼠体内的功能。尽管LPS诱导了WT AMf中的iNOS，但CD40KO AMf中未检测到iNOS的表达。此外，我们用GFP骨髓嵌合体小鼠检测了骨髓来源的祖细胞在博莱霉素诱导的肺部炎症中的作用。诱导肺部炎症导致GFP+细胞增加，积聚在活动性纤维化病变中。GFP+细胞也表达I型胶原。在此基础上，我们用一种叫Sauropus Androgynus的灌木来刺激U937的单核细胞来源细胞系。我们发现了TNF-α的产生，但没有发现CXCL9或CXCL10。提示TNF-α可能是BO发病的重要因素之一。我们的数据表明，CD40或骨髓源性祖细胞的功能阻断将成为临床治疗肺损伤（包括BO）的靶点之一。少

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 and the bone marrow-derived progenitor cells. Further, we investigate the Sauropus Androgynus-induced BO. 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, t … More he release of inflammatory mediators, that is, TNF-α,IL-1b, 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(AMf) in each of mice ex vivo. Although iNOS in WT AMf was induced in response to LPS, no iNOS expression could be detected in CD40KO AMf. In addition, we examined the role of bone marrow-derived progenitor cells in bleomycin-induced pulmonary inflammation using GFP bone marrow chimera mice. Induction of pulmonary inflammation resulted in the increase of GFP+ cells accumulated into the active fibrotic lesions. GFP+ cells also expressed type I collagen. Further, we stimulated the monocyte derived cell lines of U937 with Sauropus Androgynus, which is a leaf shrub for the cause of BO. We found the production of TNF-α, but not CXCL9 or CXCL10. These results indicated that TNF-α might be one of important factor for the pathogenesis of BO. Our data suggest that the functional blockade of CD40 or bone marrow-derived progenitor cells would yield one of the targets for the clinical treatment for lung injury including BO. Less