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

Am J Respir Cell Mol Biol. 2009 Dec;41(6):661-70. doi: 10.1165/rcmb.2008-0182OC. Epub 2009 Mar 5.

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.

MeSH terms

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

Substances

  • Antibiotics, Antineoplastic
  • IL18R1 protein, human
  • Il18r1 protein, mouse
  • Inflammation Mediators
  • Interleukin-18
  • Interleukin-18 Receptor alpha Subunit
  • Interleukin-1beta
  • RNA, Messenger
  • Bleomycin
  • Caspase 1