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

  1. Author:
    Hoshino, T.
    Okamoto, M.
    Sakazaki, Y.
    Kato, S.
    Young, H. A.
    Aizawal, H.

  2. Author Address

    Hoshino, Tomoaki, Okamoto, Masaki, Sakazaki, Yuki, Aizawal, Hisamichi] Kurume Univ, Sch Med, Dept Med, Div Respirol Neurol & Rheumatol, Kurume, Fukuoka 8300011, Japan. [Kato, Seiya] Univ Ryukyus, Div Pathol & Cell Biol, Grad Sch, Okinawa, Japan. [Kato, Seiya] Univ Ryukyus, Fac Med, Okinawa, Japan. [Hoshino, Tomoaki, Young, Howard A.] NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21701 USA.
    1. Year: 2009
  2. Journal: American Journal of Respiratory Cell and Molecular Biology
    1. 41
    2. 6
    3. Pages: 661-670
  4. Type of Article: Article
  5. ISSN: 1044-1549
  1. 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-1 beta 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-118R alpha 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-1 beta 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-1 beta 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 alpha(-/-) mice in comparison with control mice. Thus, our results provide evidence for an important role of IL-1 beta and IL-18 in chemotherapy-induced lung injury.

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  2. DOI: 10.1165/rcmb.2008-0182OC
  3. PMID: 19265174

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