PATHOPHYSIOLOGICAL ANALYSIS OF BRONCHIOLITIS OBLITERANCE USING CD40-DEFICIENT MICE AND GFP-TRANSGENIC MICE

已报告了涉及骨髓移植和心/肺移植患者以及接受或未接受青霉胺治疗的类风湿性关节炎患者的缩窄性闭塞性细支气管炎（BO）病例。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物接受者的数量不断增加，它最近已成为重新关注的焦点。为探讨BO的发病机制，本研究着重于BO小鼠实验模型的建立以及CD 40分子和骨髓源性祖细胞在BO发病中的作用。进一步研究了守宫木诱导的BO。当野生型（WT）小鼠和CD 40 KO小鼠经气管内注射LPS时，CD 40 KO小鼠中LPS诱导的肺损伤显著减少。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）的生产也被抑制在肺中的CD 40 KO小鼠。此外，t ...更多信息 CD 40 KO小鼠支气管肺泡灌洗液中TNF-α、IL-1b、巨噬细胞炎性蛋白2（MIP-2）、活性氧、氮中间体和MMP-9的释放明显减少。我们研究了离体小鼠肺泡巨噬细胞（AMf）的功能。LPS诱导WT AMf中iNOS表达，而CD 40 KO AMf中未检测到iNOS表达。此外，我们使用GFP骨髓嵌合体小鼠研究了骨髓来源的祖细胞在博来霉素诱导的肺部炎症中的作用。肺炎症的诱导导致GFP+细胞积累到活动性纤维化病变中的增加。GFP+细胞也表达I型胶原。此外，我们用守宫木刺激单核细胞衍生的细胞系U937，守宫木是引起BO的叶灌木。我们发现了TNF-α的产生，但没有CXCL 9或CXCL 10。提示TNF-α可能是BO发病的重要因素之一。我们的数据表明，CD 40或骨髓来源的祖细胞的功能性阻断将产生用于肺损伤包括BO的临床治疗的靶点之一。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