Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2.
Prostaglandin E2 (PGE2) inhibits fibroblast proliferation and collagen synthesis. In this study, we compared lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (F-IPF) and from patients undergoing resectional surgery for lung cancer (F-nl) with respect to their capacity for PGE2 synthesis and their expression and regulation of cyclooxygenase (COX) proteins. Basal COX activity, assessed by quantitating immunoreactive PGE2 synthesized from arachidonic acid, was twofold less (P < 0.05) in F-IPF than F-nl. In F-nl, incubation with the agonists PMA, LPS, or IL-1 increased COX activity and protein expression of the inducible form of COX, COX-2, and these responses were inhibited by coincubation with dexamethasone. By contrast, F-IPF failed to demonstrate increases in COX-2 protein expression or COX activity in response to these agonists. Under conditions of maximal induction, COX activity in F-IPF was sixfold less than that in F-nl (P < 0.05). Our data indicate that F-IPF have a striking defect in their capacity to synthesize the antiinflammatory and antifibrogenic molecule PGE2, apparently because of a diminished induction of COX-2 protein. This reduction in the endogenous capacity of F-IPF to down-regulate their function via PGE2 may contribute to the inflammatory and fibrogenic response in IPF. Moreover, we believe that this represents the first description of a defect in COX-2 expression in association with a human disease.
Wilborn
J
J
Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, USA.
Crofford
L J
LJ
Burdick
M D
MD
Kunkel
S L
SL
Strieter
R M
RM
Peters-Golden
M
M
D001483:Base Sequence; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis*; D015777:Eicosanoids / Q000032:analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007375:Interleukin-1 / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000737:chemistry / Q000166:cytology*; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D015777:Eicosanoids; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011451:Prostaglandin-Endoperoxide Synthases; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate