Prostaglandin E2 protects human lung fibroblasts from cigarette smoke extract‐induced apoptosis via EP2 receptor activation

Prostaglandin E2 (PGE2) has been shown to have a strong cytoprotective effect, inhibiting apoptosis. In the present study, we evaluated whether PGE2 has a protective effect on cigarette smoke extract (CSE)‐induced apoptosis in human lung fibroblasts. Apoptosis was assessed by various methods, including DNA content analysis. CSE (15%–20%) led to apoptosis and induced imbalance in favor of pro‐ over anti‐apoptotic protein expression and activated caspases. PGE2 blocked CSE‐induced apoptosis and modulated the balance of pro‐ and anti‐apoptotic proteins and decreased the activation of caspases. This anti‐apoptotic effect was mediated via EP2 receptor activation as the EP2 agonist butaprost mimicked PGE2 activity and siRNA for the EP2 receptor blocked it. An adenylyl cyclase inhibitor was found to abolish the PGE2‐mediated cytoprotective effect. Correspondingly, c‐AMP analogs blocked CSE‐induced apoptosis. Consistently, the protein kinase A (PKA) inhibitor KT‐5720 abolished PGE2‐mediated protection. PGE2 and butaprost phosphorylated Bad and KT‐5720 blocked phosphorylation. These results suggest that PGE2 inhibits CSE‐induced apoptosis via EP2 receptor activation and activation of PKA, which leads to an alteration in the balance between pro‐ and anti‐apoptotic factors. Through such a mechanism, PGE2 may alter survival of cells in the smoke‐exposed lungs, thus affecting the pathogenesis of cigarette smoke‐induced disease. J. Cell. Physiol. 210: 99–110, 2007. © 2006 Wiley‐Liss, Inc.

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