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in the Evolution of Murine Bleomycin Lung Fibrosis
1 Hadassah University Hospital and Hebrew University-Hadassah Medical School, Lung Cellular & Molecular Biology Laboratory, Institute of Pulmonology, Jerusalem, Israel
2 Bone Marrow Transplantation Department, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel
3 Department of Pathology, Mallory Institute of Pathology, Boston University School of Medicine, Boston, MA, USA
4 Hadassah University Hospital and Hebrew University-Hadassah Medical School, Lung Cellular & Molecular Biology Laboratory, Institute of Pulmonology, Jerusalem, Israel; Department of Pathology, Mallory Institute of Pathology, Boston University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: raffi{at}hadassah.org.il.
IFN-
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- expression in bleomycin-induced lung injury. IFN- mRNA in LC from bleomycin-treated mice peaked 3d after intratracheal instillation. IFN- protein levels were increased at 6d, as was the percentage of LC expressing IFN-. CD4+, CD8+
and NK cells each contributed significantly to IFN- production. IL-12 mRNA levels were increased at 1d in LC of bleomycin treated mice. Anti-IL-12 and anti-IL-18 antibodies decreased IFN- production by these cells. To define the role of endogenous IFN- in the evolution of bleomycin lung injury, we compared the effect of bleomycin in mice with a targeted knockout mutation of the IFN- gene (IFN-
knockout) and wild-type mice. At 14d after intratracheal bleomycin, total BAL cell counts and lung hydroxyproline were decreased in IFN- knockouts compared to
wild-type animals. There was no difference in morphometric parameters of fibrosis. Our data show that enhanced IFN- production in the lungs of bleomycin treated mice
is at least partly IL-12 and IL-18 dependent. Absence of IFN- in IFN- knockout mice does not increase pulmonary fibrosis. Endogenous IFN- may play a proinflammatory or pro-fibrotic role in bleomycin-induced lung fibrosis.
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