| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
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
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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
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