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

Abstract

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.