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Am J Physiol Lung Cell Mol Physiol 285: L1255-L1262, 2003. First published July 11, 2003; doi:10.1152/ajplung.00303.2002
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Role of interferon-{gamma} in the evolution of murine bleomycin lung fibrosis

Michael J. Segel,1 Gabriel Izbicki,1 Pazit Y. Cohen,1 Reuven Or,2 Thomas G. Christensen,3 Shulamit B. Wallach-Dayan,1 and Raphael Breuer1,3

1Lung Cellular & Molecular Biology Laboratory, Institute of Pulmonology, 2Bone Marrow Transplantation Department, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; and 3Mallory Institute of Pathology, Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118

Submitted 14 September 2002 ; accepted in final form 27 June 2003

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.

interstitial lung disease; transgenic/knockout; cytokines


Address for reprint requests and other correspondence: R. Breuer, Inst. of Pulmonology, Hadassah Univ. Hospital, POB 12000, Jerusalem 91120, Israel (E-mail: raffi{at}hadassah.org.il).




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