Journal
JOURNAL OF IMMUNOLOGY
Volume 165, Issue 7, Pages 4032-+Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.165.7.4032
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Funding
- NCI NIH HHS [R29CA79046] Funding Source: Medline
- NHLBI NIH HHS [HL062124, HL57885] Funding Source: Medline
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To characterize the role of GM-CSF in pulmonary fibrosis, we have studied bleomycin-induced fibrosis in wild-type mice vs mice with a targeted deletion of the GM-CSF gene (GM-CSF-/- mice). Without GM-CSF, pulmonary fibrosis was worse both histologically and quantitatively, These changes were not related to enhanced recruitment of inflammatory cells because wild-type and GM-CSF-/- mice recruited equivalent numbers of cells to the lung following bleomycin. Interestingly, recruitment of eosinophils was absent in GM-CSF-/- mice. We investigated whether the enhanced fibrotic response in GM-CSF-/- animals was due to a deficiency in an endogenous down-regulator of fibrogenesis. Analysis of whole lung homogenates from saline- or bleomycin-treated mice revealed that GM-CSF-/- animals had reduced levels of PGE(2). Additionally, alveolar macrophages were harvested from wild-type and GM-CSF-/- mice that had been exposed to bleomycin. Although bleomycin treatment impaired the ability of alveolar macrophages from wild-type mice to synthesize PGE(2), alveolar macrophages from GM-CSF-/- mice exhibited a significantly greater defect in PGE(2) synthesis than did wild-type cells. Exogenous addition of GM-CSF to alveolar macrophages reversed the PGE(2) synthesis defect in vitro. Administration of the PG synthesis inhibitor, indomethacin, to wild-type mice during the fibrogenic phase postbleomycin worsened the severity of fibrosis, implying a causal role for PGE(2) deficiency in the evolution of the fibrotic lesion. These data demonstrate that GM-CSF deficiency results in enhanced fibrogenesis in bleomycin-induced pulmonary fibrosis and indicate that one mechanism for this effect is impaired production of the potent antifibrotic eicosanoid, PGE(2).
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