Attenuation of Lung Inflammation and Fibrosis in Interferon- γ –Deficient Mice after Intratracheal Bleomycin

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 morta...