CULTURED LUNG FIBROBLASTS ISOLATED FROM PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS HAVE A DIMINISHED CAPACITY TO SYNTHESIZE PROSTAGLANDIN E(2), AND TO EXPRESS CYCLOOXYGENASE-2

Prostaglandin E(2) (PGE(2)) inhibits fibroblast proliferation and coll agen synthesis, In this study, we compared lung fibroblasts isolated f rom patients with idiopathic pulmonary fibrosis (F-IPF) and from patie nts undergoing resectional surgery for lung cancer (F-nl) with respect to their capacity for PGE(2) synthesis and their expression and regul ation of cyclooxygenase (COX) proteins, Basal COX activity, assessed b y quantitating immunoreactive PGE(2) 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 w ere inhibited by coincubation with dexamethasone, By contrast, F-IPF f ailed to demonstrate increases in COX-2 protein expression or COX acti vity in response to these agonists, Under conditions of maximal induct ion, COX activity in F-IPF was sixfold less than that in F-nl (P < 0.0 5), Our data indicate that F-IPF have a striking defect in their capac ity to synthesize the antiinflammatory and antifibrogenic molecule PGE ,, 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 PGE, may contribute to the inflammatory and fibrogenic re sponse in IPF. Moreover, we believe that this represents the first des cription of a defect in COX-2 expression in association with a human d isease.