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1 Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
2 Department of Internal Medicine, Veteran's Affairs Medical Center, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: bmoore{at}umich.edu.
Prostaglandin E2 (PGE2 ) is a potent suppressor of fibroblast activity. We previously reported that bleomycin-induced pulmonary fibrosis was exaggerated in granulocyte-macrophage colony-stimulating factor knock-out (GM-CSF-/-) mice as compared to wild-type (GM-CSF+/+) mice, and that increased fibrosis was associated with decreased PGE2 levels in lung homogenates and alveolar macrophage cultures. Pulmonary fibroblasts and alveolar epithelial cells (AECs) represent additional cellular sources of PGE2 within the lung. Therefore, we examined fibroblasts and AECs from GM-CSF-/- mice and we found that they elaborated significantly less PGE2 than did cells from GM-CSF+/+ mice. This defect was associated with reduced expression of cyclooxygenase-1 and -2 (COX-1 and COX-2), key enzymes in the biosynthesis of PGE2. Additionally, proliferation of GM-CSF-/- fibroblasts was greater than that of GM-CSF+/+ fibroblasts, and GM-CSF-/- AECs were impaired in their ability to inhibit fibroblast proliferation in coculture. The addition of GM-CSF to fibroblasts from GM-CSF-/- mice increased PGE2 production and decreased proliferation. Simiarly, AECs isolated from SpC-GM mice (GM-CSF-/- mice with transgenic expression of GM-CSF under the SpC promoter) produced more PGE2 than did AEC from control mice. Finally, SpC-GM mice were protected from fluorescein isothiocyanate-induced pulmonary fibrosis. In conclusion, these data demonstrate that GM-CSF regulates PGE2 production in pulmonary fibroblasts and AECs, and thus plays an important role in limiting fibroproliferation.
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