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Bleomycin-Induced Pulmonary Fibrosis Is Attenuated in Interferon-γ Knockout Mice* FREE TO VIEW

Edward S. Chen, MD; Brian M. Greenlee, BS; Marsha Wills-Karp, PhD; David R. Moller, MD
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*From the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD.

Correspondence to: Edward S. Chen, MD, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, Baltimore, MD 21224

Chest. 2001;120(1_suppl):S8. doi:10.1378/chest.120.1_suppl.S8
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(CHEST 2001; 120:8S)

Since mouse strains susceptible to bleomycin, such as C57BL/6J, tend to produce T-helper 1 cytokines in response to immune activation, we hypothesized that the inflammatory response to bleomycin is mediated, in part, by local production of the T-helper 1 cytokine, interferon (IFN)-γ. We determined that IFN-γ is expressed in BAL fluid 12 to 24 h following bleomycin exposure in bleomycin-susceptible C57BL/6J and A/J mice (p < 0.05) but not bleomycin-resistant BALB/c mice. The early expression of IFN-γ was associated with increased lung inflammation, weight loss, and mortality 10 days following 5 U/kg of intratracheal bleomycin instillation in C57BL/6J and A/J mice compared with BALB/c mice or control mice receiving saline solution. The T-helper 2 cytokine, interleukin-4, was either not detected or detected at minimal levels in BAL fluid from mice in all groups. To directly determine a role for IFN-γ in mediating the inflammatory or fibrotic response to bleomycin, C57BL/6J mice with a homozygous null mutation of the IFN-γ gene (IFN-[–/–]) and wild-type C57BL/6J mice were exposed to either 5 U/kg or 1.5 U/kg of bleomycin or saline solution. IFN-γ(−/−) mice demonstrated significantly lower parenchymal inflammation (p < 0.05) and mortality (p < 0.0001) following 5 U/kg of intratracheal bleomycin instillation compared with C57BL/6J control mice. At 10 days following bleomycin administration, there was no difference in total lung collagen as determined by hydroxyproline assay. Since the lack of difference in collagen content at 10 days could reflect insufficient time for any potential differences in the fibrotic processes to be manifest, we evaluated mice at 3 weeks following exposure to lower doses of bleomycin that would produce less mortality. At 3 weeks following lower-dose 1.5 U/kg of intratracheal bleomycin treatment, IFN-γ (−/−) mice demonstrated significantly lower parenchymal inflammation (p < 0.05), mortality (p < 0.05), weight loss (p < 0.005), and total lung hydroxyproline content (p < 0.005) compared with control C57BL/6J mice. Together, these results suggest that IFN-γ mediates, in part, bleomycin-induced pulmonary inflammation and fibrosis. The effects of locally produced IFN-γ may potentiate the toxicity associated with bleomycin exposure that results in enhanced pulmonary fibrosis following increased lung injury.

Abbreviation: IFN = interferon




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