Administration of several chemotherapeutic drugs such as bleomycin, busulfan, and gefitinib often induces lethal lung injury. However, the precise mechanisms responsible for this drug-induced lung injury are still unclear. In the present study, we examined the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury. We performed immunohistochemical analysis of IL-18 and IL-18 receptoralpha (Ralpha) chain expression in the lungs of 5 patients with bleomycin-induced lethal lung injury. Enhanced expression of both IL-18 and IL-18Ralpha was observed in the lungs of all 5 patients with bleomycin-induced lung injury. To support the data obtained from patient samples, the levels of IL-1beta and IL-18 mRNA and protein, pulmonary inflammation, and lung fibrosis were examined in mouse models of bleomycin-induced lung injury. Intravenous administration of bleomycin induced the expression of IL-1beta and IL-18 in the serum and lungs of wild-type C57BL/6 (B6) mice. IL-18-producing F4/80+ neutrophils, but not CD3+ T cells, were greatly increased in the lungs of treated mice. Moreover, bleomycin-induced lung injury was significantly attenuated in caspase-1 (-/-), IL-18 (-/-), and IL-18Ralpha (-/-) mice, in comparison with control mice. Thus our results provide evidence for an important role of IL-1beta and IL-18 in chemotherapy-induced lung injury.