Attenuation of lung inflammation and fibrosis in interferon-γ-deficient mice after intratracheal bleomycin

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Abstract

Because mouse strains susceptible to bleomycin, such as C57BL/6J, tend to produce T helper type 1 (Th1) cytokines in response to immune activation, we hypothesized that the inflammatory response to bleomycin is mediated, in part, by local production of the Th1 cytokine interferon-γ (IFN-γ). Consistent with this hypothesis, fibrosis-prone C57BL/6J and A/J mice demonstrated significantly elevated expression of IFN-γ protein (by enzyme-linked immunosorbent assay) in bronchoalveolar lavage fluid at 24 h, and subsequently increased lung inflammation, weight loss, and mortality 10 d after intratracheal bleomycin administration compared with fibrosis-resistant BALB/c mice or saline control mice. To directly determine a role for IFN-γ in bleomycin toxicity, we exposed C57BL/6J mice with a homozygous null mutation of the IFN-γ gene (IFN-γ[-/-]) and wild-type C57BL/6J mice to intratracheal bleomycin. IFN-γ(-/-) mice demonstrated significantly lower parenchymal inflammation, weight loss, and mortality 10 d after 5 U/kg intratracheal bleomycin administration compared with control mice. At 3 wk after 1.5 U/kg bleomycin exposure, single lung lagen determined by hydroxyproline assay was significantly lower in IFN-γ(-/-) mice compared with wild-type C57BL/6J mice. Together, these results suggest that IFN-γ mediates, in part, bleomycin-induced pulmonary inflammation and fibrosis.

Original languageEnglish (US)
Pages (from-to)545-555
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume24
Issue number5
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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