Am. J. Respir. Cell Mol. Biol., Volume 24, Number 5, May, 2001 545-555

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

Edward S. Chen, Brian M. Greenlee, Marsha Wills-Karp, and David R. Moller

Division of Pulmonary and Critical Care Medicine, Department of Medicine and Department of Environmental Health Sciences, The Johns Hopkins University, Baltimore, Maryland

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- (IFN-). Consistent with this hypothesis, fibrosis-prone C57BL/6J and A/J mice demonstrated significantly elevated expression of IFN- 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- in bleomycin toxicity, we exposed C57BL/6J mice with a homozygous null mutation of the IFN- gene (IFN-[/]) and wild-type C57BL/6J mice to intratracheal bleomycin. IFN-(/) 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 collagen determined by hydroxyproline assay was significantly lower in IFN-(/) mice compared with wild-type C57BL/6J mice. Together, these results suggest that IFN- mediates, in part, bleomycin-induced pulmonary inflammation and fibrosis.

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