Although PGE 2 is a potent inhibitor of fibroblast function, PGE 2 levels are paradoxically elevated in murine lungs undergoing fibrotic responses. Pulmonary fibroblasts from untreated mice expressed all four E prostanoid (EP) receptors for PGE 2. However, following challenge with the fibrogenic agent, bleomycin, fibroblasts showed loss of EP2 expression. Lack of EP2 expression correlated with an inability of fibroblasts from bleomycin-treated mice to be inhibited by PGE 2 in assays of proliferation or collagen synthesis and blunted cAMP elevations in response to PGE 2. PGE 2 was similarly unable to suppress proliferation or collagen synthesis in fibroblasts from EP2−/− mice despite expression of the other EP receptors. EP2−/−, but not EP1−/− or EP3−/− mice, showed exaggerated fibrotic responses to bleomycin administration in vivo as compared with wild-type controls. EP2 loss on fibroblasts was verified in a second model of pulmonary fibrosis using FITC. Our results for the first time link EP2 receptor loss on fibroblasts following fibrotic lung injury to altered suppression by PGE 2 and thus identify a novel fibrogenic mechanism.