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Pulmonary fibrosis is characterized by fibroblasts persisting in an activated form, producing excessive fibrous material that destroys alveolar structure. The second messenger molecule cyclic 3',5'-adenosine monophosphate (cAMP) has antifibrotic properties, and prostaglandin E 2 (PGE 2 ) can stimulate cAMP production through prostaglandin E (EP) 2 and EP 4 receptors. Although EP receptors are attractive therapeutic targets, the effects of long-term exposure to PGE 2 have not been characterized. To determine the effects of long-term exposure of lung fibroblasts to PGE 2 , human fetal lung (HFL)-1 cells were treated for 24 h with 100 nM PGE 2 or other cAMP-elevating agents. cAMP levels stimulated by acute exposure to PGE 2 were measured using a fluorescent biosensor. Pretreatment for 24 h with PGE 2 shifted the concentration-response curve to PGE 2 rightward by approximately 22-fold but did not affect responses to the beta-adrenoceptor agonist isoproterenol. Neither isoproterenol nor forskolin pretreatment altered PGE 2 responses, implying that other cAMP-elevating agents do not induce desensitization. Use of EP 2 - and EP 4 -selective agonists and antagonists suggested that PGE 2 -stimulated cAMP responses in HFL-1 cells are mediated by EP 2 receptors. EP 2 receptors are resistant to classical mechanisms of agonist-specific receptor desensitization, so we hypothesized that increased PDE activity mediates the loss of signaling after PGE 2 pretreatment. PGE 2 treatment upregulated messenger RNA for PDE3A, PDE3B, PDE4B, and PDE4D and increased overall PDE activity. The PDE4 inhibitor rolipram partially reversed PGE 2 -mediated desensitization and PDE4 activity was increased, but rolipram did not alter responses to isoproterenol. The PDE3 inhibitor cilostazol had minimal effect. These results show that long-term exposure to PGE 2 causes agonist-specific desensitization of EP 2 receptor-stimulated cAMP signaling through the increased expression of PDE isozymes, most likely of the PDE4 family.

Agonist-specific desensitization of PGE2-stimulated cAMP signaling due to upregulated phosphodiesterase expression in human lung fibroblasts