Dysfunction of COX-2/mPGES-1/PGE2 pathway and EP4 receptor in bronchi from COPD patients.

Progressive airflow obstruction and chronic lung inflammation are hallmarks of chronic obstructive pulmonary disease (COPD). Prostaglandin E2 (PGE2), synthesized by the cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), acts as a lipid mediator with bronchodilatory effects mediated by the EP4 receptor. Altered expression and function of COX-2, mPGES-1, PGE2 and EP receptors may contribute to the pathophysiology of COPD. This study investigates whether COPD is associated with dysregulated expression or function of COX-2, mPGES-1, EP receptors and PGE2 production in human bronchi. We analyzed the expression of COX-2, mPGES-1, PGE2 and EP receptors in human bronchi samples using Western blot, real-time qPCR, ELISA and immunohistochemistry (IHC). Our results reveal significantly elevated COX-2 protein, mPGES-1 mRNA, and PGE2 levels in COPD patients compared to controls. Conversely, in COPD preparations EP4 receptor mRNA and protein levels were markedly reduced, a result confirmed by IHC. In addition, IHC also showed that the EP4 receptor was mainly localized in the epithelium of control bronchi. Notably, there was a significant negative correlation between EP4 and PGE2 levels. The hypothesis of EP4 internalization due to increased PGE2 in COPD patients is credible. These data demonstrate a significant alteration of the COX-2/mPGES-1/PGE2/EP4 pathway in COPD and suggest that pharmacological targeting of this pathway may be of interest to treat COPD.