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      Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice.

      American journal of respiratory cell and molecular biology
      Acute Lung Injury, chemically induced, genetics, metabolism, pathology, Aged, Animals, Antibiotics, Antineoplastic, administration & dosage, adverse effects, toxicity, Bleomycin, Caspase 1, deficiency, Disease Models, Animal, Female, Humans, Inflammation Mediators, blood, Injections, Intravenous, Interleukin-18, Interleukin-18 Receptor alpha Subunit, Interleukin-1beta, Lung, drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Neutrophils, RNA, Messenger

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          Abstract

          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 receptor (R) alpha chain expression in the lungs of five patients with bleomycin-induced lethal lung injury. Enhanced expression of both IL-18 and IL-18Ralpha was observed in the lungs of all five 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 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.

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