Role of interferon-gamma in the evolution of murine bleomycin lung fibrosis

Am J Physiol Lung Cell Mol Physiol. 2003 Dec;285(6):L1255-62. doi: 10.1152/ajplung.00303.2002. Epub 2003 Jul 11.

Abstract

IFN-gamma production is upregulated in lung cells (LC) of bleomycin-treated C57BL/6 mice. The present study characterizes the time course, cellular source, and regulation of IFN-gamma expression in bleomycin-induced lung injury. IFN-gamma mRNA in LC from bleomycin-treated mice peaked 3 days after intratracheal instillation. IFN-gamma protein levels were increased at 6 days, as was the percentage of LC expressing IFN-gamma. CD4+, CD8+, and natural killer cells each contributed significantly to IFN-gamma production. IL-12 mRNA levels were increased at 1 day in LC of bleomycin-treated mice. Anti-IL-12 and anti-IL-18 antibodies decreased IFN-gamma production by these cells. To define the role of endogenous IFN-gamma in the evolution of bleomycin lung injury, we compared the effect of bleomycin in mice with a targeted knockout mutation of the IFN-gamma gene (IFN-gamma knockout) and wild-type mice. At 14 days after intratracheal bleomycin, total bronchoalveolar lavage cell counts and lung hydroxyproline were decreased in IFN-gamma knockouts compared with wild-type animals. There was no difference in morphometric parameters of fibrosis. Our data show that enhanced IFN-gamma production in the lungs of bleomycin-treated mice is at least partly IL-12 and IL-18 dependent. Absence of IFN-gamma in IFN-gamma knockout mice does not increase pulmonary fibrosis. Endogenous IFN-gamma may play a proinflammatory or profibrotic role in bleomycin-induced lung fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic
  • Bleomycin
  • Bronchoalveolar Lavage Fluid
  • Flow Cytometry
  • Gene Expression / immunology
  • Interferon-gamma / genetics*
  • Interferon-gamma / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / immunology*
  • Pulmonary Fibrosis / physiopathology*
  • RNA, Messenger / analysis

Substances

  • Antimetabolites, Antineoplastic
  • RNA, Messenger
  • Bleomycin
  • Interferon-gamma