Budget Amount *help |
¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
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Research Abstract |
To investigate the role of kinin-kallikein system in chronic inflammatory pulmonary diseases, we studied the molecular biological function of bradykinin B1 receptor in vitro and ex vivo. Bradykinin receptor has two subtypes B1 and B2, which are inducible and constitutive receptors for des-Arg^9-bradykinin and des-Arg^10-kallidin and for bradykinin and kallidin, B1 and B2 receptor agonists, respectively. First we characterized murine B1 receptor in a murine alveolar macrophage cell line MH-S. Pro-inflammatory cytokine interleukin-1__.β(IL -1__.β)induced murine B1 receptor gene expression assessed by quantitative real time RT-PCR, and B1 agonist stimulated the production of tumor necrosis factor alpha (TNF-α) by IL-1__.β-pretreated MH-S cells. Then we characterized human Bl receptor in human lung fibroblast cell line IMR-90. IL-1__.βinduced human Bl receptor gene expression assessed by quantitative real time RT-PCR, and Bl agonist stimulated the production of extracellular matrix fibronectin by IMR-90 cells. With Bl receptor agonist stimulation IL-1__.β-pretreated IMR-90 cells produced less fibronectin than that of IL-1__.β-untreated IMR-90 cells. This interesting phenomenon was reversed by cyclooxygenase (COX) inhibitors indomethacin and NS-398, the dual COX1/COX-2 inhibitor and selective COX-2 inhibitor, respectively. Furthermore, there was a decrease in the gene expression of B1 receptor in the lung tissue of idiopathic pulmonary fibrosis patients compared to the control. These results suggest that kinin-kallikrein system play some role in the chronic inflammatory pulmonary diseases via B1 receptor activation to protect lung fibrosis in combination with inducible COX-2. Because there are some polymorphisms in B1 receptor gene in other diseases, further investigation would be needed in chronic inflammatory pulmonary diseases as well especially in idiopathic pulmonary fibrosis.
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