|Budget Amount *help
¥12,800,000 (Direct Cost : ¥12,800,000)
Fiscal Year 2004 : ¥6,100,000 (Direct Cost : ¥6,100,000)
Fiscal Year 2003 : ¥6,700,000 (Direct Cost : ¥6,700,000)
Rationale : Administration of several chemotherapeutic drugs such as bleomycin, busulfan, and gefitinib often induces lethal lung injury. IL-1β and IL-18, members of the IL-1 family, are produced from a biologically inactive precursor and secreted from macrophages after cleavage by caspase-1. We established a new mouse model for human interstitial lung diseases in which daily administration of IL-18 with IL-2 induced lethal lung injury. Recently, we reported an increased level of IL-18 and IL-18Rα expression in the lungs of patients with idiopathic pulmonary fibrosis. Objectives : The aim of our present study was to evaluate the roles of IL-1β and IL-18 in the pathogenesis of bleomycin-induced lung injury. Methods : We investigated whether IL-1R and IL-18 secretion induced by bleomycin causes lung injury in caspase-1 deficient (-/-), IL-18 (-/-), and IL-18Ra (-/-) mice, and in humans. Measurement and Main Results: Intravenous administration of bleomycin induced the expression of IL-1β, IL-18, and various cytokines and chemokines (e.g. MIP-2, IP-10, MCP-1, and TCA-3) in the serum and lungs of normal mice. Macrophages (Kupffer cells) isolated from wild-type mice, but not caspase-1 (-/-) mice, secreted IL-1βand IL-18 upon stimulation with bleomycin in vitro. Bleomycin-induced lung injury was prevented in caspase-1 (-/-), IL-18 (-/-), and IL-18Rα (-/-) mice, but not in control mice. Moreover, enhanced expression of IL-18 and IL-18Rα was observed in the lungs of patients with bleomycin-induced lung injury. Conclusions : Our results suggest IL-1β and IL-18 secretion in the lungs may cause severe lung injury as a consequence of treatment with some chemotherapeutic drugs.