Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent.
Alveolar epithelial cells (AECs) may influence neighboring fibroblasts by the elaboration of prostaglandin E(2) (PGE(2)). This prostanoid can be synthesized via "constitutive" cyclooxygenase (COX)-1 and "inducible" COX-2 enzyme isoforms. We compared AECs isolated from wild-type (WT), COX-1 knockout (KO), and COX-2 KO mice to determine the contribution of COX isoforms to AEC PGE(2) synthesis and capacity for suppression of fibroblast proliferation in co-cultures. WT AECs constitutively expressed both COX-1 and COX-2 isoforms by immunoblot analysis. COX-1 KO cells and WT cells comparably augmented PGE(2) synthesis following incubation with lipopolysaccharide or interleukin-1, whereas COX-2 KO cells were unable to do so. Surprisingly, however, constitutive generation of PGE(2) was also dramatically reduced only in COX-2 KO cells. When co-cultured with WT murine lung fibroblasts, AECs from WT and COX-1 KO animals suppressed serum-induced fibroblast proliferation, whereas COX-2-deficient AECs caused a modest enhancement in fibroblast proliferation. These results indicate that PGE(2) synthetic capacity in AECs is predominantly COX-2-dependent under both basal and stimulated conditions. They also demonstrate conclusively that AECs can modulate fibroblast function by the elaboration of suppressive prostanoids. These alterations in AEC phenotype likely contribute to the propensity for pulmonary fibrosis observed in COX-2-deficient mice.
Lama
Vibha
V
Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor 48109-0642, USA.
Moore
Bethany B
BB
Christensen
Paul
P
Toews
Galen B
GB
Peters-Golden
Marc
M
D000818:Animals; D002450:Cell Communication / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D005347:Fibroblasts / Q000166:cytology*; D005838:Genotype; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology* / Q000201:enzymology*
D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone