GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandin-dependent mechanism.
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 PGE2. 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 PGE2, alveolar macrophages from GM-CSF-/- mice exhibited a significantly greater defect in PGE2 synthesis than did wild-type cells. Exogenous addition of GM-CSF to alveolar macrophages reversed the PGE2 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 PGE2 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, PGE2.
Moore
B B
BB
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109, USA. Bmoore@umich.edu
Coffey
M J
MJ
Christensen
P
P
Sitterding
S
S
Ngan
R
R
Wilke
C A
CA
McDonald
R
R
Phare
S M
SM
Peters-Golden
M
M
Paine
R
R
Toews
G B
GB
D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000494:pharmacology*; D002455:Cell Division / Q000235:genetics; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency; D004334:Drug Administration Schedule; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007213:Indomethacin / Q000008:administration & dosage; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007442:Intubation, Intratracheal; D007700:Kinetics; D007958:Leukocyte Count; D017997:Leukotriene C4 / Q000096:biosynthesis / Q000172:deficiency; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D011453:Prostaglandins / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D012965:Sodium Chloride / Q000008:administration & dosage
D008055:Lipids; D011453:Prostaglandins; D001761:Bleomycin; D017997:Leukotriene C4; D012965:Sodium Chloride; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone; D007213:Indomethacin