Modulation of collagen production following bleomycin-induced pulmonary fibrosis in hamsters. Presence of a factor in lung that increases fibroblast prostaglandin E2 and cAMP and suppresses fibroblast proliferation and collagen production.
To elucidate mechanisms involved in the regulation of lung collagen content we studied hamsters with bleomycin-induced pulmonary fibrosis. Lung collagen in this model is increased as the result of greatly increased lung collagen synthesis rates. However, collagen synthesis rates are subsequently restored to normal. Hamster lung explants from both normal and bleomycin-exposed hamsters were cultured, and the effects of explant conditioned medium (CM) on lung fibroblast (IMR-90) proliferation and collagen production in vitro were determined. Lung explant CM increased fibroblast prostaglandin (PG)E2 production and intracellular cAMP, and decreased both fibroblast proliferation and collagen production in a dose-dependent manner. Greater activity was observed with lung explant CM from bleomycin-exposed lungs. Incubation of fibroblasts with indomethacin prior to addition of CM blocked CM-mediated changes in PGE2 and cAMP and inhibited changes in fibroblast proliferation and collagen production. Exogenous PGE2 or dibutyryl cAMP also suppressed fibroblast proliferation and collagen production. The suppressive activity in lung-conditioned medium is nondialyzable, has an apparent molecular weight of 15,000-20,000 by gel filtration, and is heat-stable. It is not species-restricted since CM from hamster lung affected human and hamster lung fibroblasts similarly. Activity is present preformed in lung and bronchoalveolar lavage fluid, although bronchoalveolar macrophages produce a nondialyzable factor in culture which suppresses fibroblast proliferation. The suppressive activity identified in fibrotic lung may represent a means for limiting collagen accumulation following tumor injury.
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D015232:Dinoprostone; D005260:Female; D005333:Fetus; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D011247:Pregnancy; D011458:Prostaglandins E / Q000096:biosynthesis*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*
D011458:Prostaglandins E; D001761:Bleomycin; D003094:Collagen; D000242:Cyclic AMP; D015232:Dinoprostone