This Article Full Text Full Text (PDF) All Versions of this Article: 2008-0182OCv1 41/6/661    most recent Alert me when this article is cited Alert me if a correction is posted Services Related articles in AJRCMB Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Hoshino, T. Articles by Aizawa, H. PubMed PubMed Citation Articles by Hoshino, T. Articles by Aizawa, H.

Role of Proinflammatory Cytokines IL-18 and IL-1β in Bleomycin-Induced Lung Injury in Humans and Mice

¹ Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka; ² Division of Pathology and Cell Biology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan; and ³ Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute–Frederick, Frederick, Maryland

Correspondence and requests for reprints should be addressed to Tomoaki Hoshino, M.D., Ph.D., Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan. E-mail: hoshino{at}med.kurume-u.ac.jp

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-1β in the mechanism of bleomycin-induced lung injury. We performed immunohistochemical analysis of IL-18 and IL-18 receptor (R) chain expression in the lungs of five patients with bleomycin-induced lethal lung injury. Enhanced expression of both IL-18 and IL-18R 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-1β 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-1β 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-18R^–/– mice in comparison with control mice. Thus, our results provide evidence for an important role of IL-1β and IL-18 in chemotherapy-induced lung injury.

Key Words: bleomycin • lung injury • cytokine • mouse model

CLINICAL RELEVANCE Enhanced expression of both IL-18 and IL-18 receptor (R) was observed in the lungs of all five patients with bleomycin-induced lung injury. IL-18–producing F4/80+ macrophages, but not CD3+ T cells, were greatly increased in the lungs of bleomycin-treated mice. Moreover, bleomycin-induced lung injury was significantly attenuated in caspase-1–/–, IL-18–/–, and IL-18R–/– mice in comparison with control mice. Our results provide evidence for an important role of IL-1β and IL-18 in chemotherapy-induced lung injury.

 

Related articles in AJRCMB:

Highlights of the December Issue

Kenneth B. Adler and Sadis Matalon
AJRCMB 2009 41: 629-630. [Full Text]  

This article has been cited by other articles:

				K. B. Adler and S. Matalon Highlights of the December Issue Am. J. Respir. Cell Mol. Biol., December 1, 2009; 41(6): 629 - 630. [Full Text] [PDF]