Impaired synthesis of prostaglandin E2 by lung fibroblasts and alveolar epithelial cells from GM-CSF-/- mice: implications for fibroproliferation.
Prostaglandin E(2) (PGE(2)) is a potent suppressor of fibroblast activity. We previously reported that bleomycin-induced pulmonary fibrosis was exaggerated in granulocyte-macrophage colony-stimulating factor knockout (GM-CSF(-/-)) mice compared with wild-type (GM-CSF(+/+)) mice and that increased fibrosis was associated with decreased PGE(2) levels in lung homogenates and alveolar macrophage cultures. Pulmonary fibroblasts and alveolar epithelial cells (AECs) represent additional cellular sources of PGE(2) within the lung. Therefore, we examined fibroblasts and AECs from GM-CSF(-/-) mice, and we found that they elaborated significantly less PGE(2) 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 PGE(2). 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 PGE(2) production and decreased proliferation. Similarly, AECs isolated from GM-CSF(-/-) mice with transgenic expression of GM-CSF under the surfactant protein C promoter (SpC-GM mice) produced more PGE(2) 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 PGE(2) production in pulmonary fibroblasts and AECs and thus plays an important role in limiting fibroproliferation.
Charbeneau
Ryan P
RP
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
Christensen
Paul J
PJ
Chrisman
Cara J
CJ
Paine
Robert
R
Toews
Galen B
GB
Peters-Golden
Marc
M
Moore
Bethany B
BB
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis* / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D010741:Phospholipases A / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism
D007527:Isoenzymes; D008565:Membrane Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D010741:Phospholipases A; D015232:Dinoprostone