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.