Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice.
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.
Hoshino
Tomoaki
T
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
Okamoto
Masaki
M
Sakazaki
Yuki
Y
Kato
Seiya
S
Young
Howard A
HA
Aizawa
Hisamichi
H
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
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