title: Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice.
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.
authors.affiliation: Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan. hoshino@med.kurume-u.ac.jp
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hoshino
authors.forename: Masaki
authors.initials: M
authors.lastname: Okamoto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sakazaki
authors.forename: Seiya
authors.initials: S
authors.lastname: Kato
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Aizawa
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000633:toxicity; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects* / Q000633:toxicity; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D007275:Injections, Intravenous; D020382:Interleukin-18 / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C508572:IL18R1 protein, human; C508573:Il18r1 protein, mouse; D018836:Inflammation Mediators; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D053583:Interleukin-1beta; D012333:RNA, Messenger; D001761:Bleomycin; D020170:Caspase 1