Reduced miR-146a Increases Prostaglandin E2 in Chronic Obstructive Pulmonary Disease Fibroblasts

Rationale: Persistent inflammation plays a major role in chronic obstructive pulmonary disease (COPD) pathogenesis, but its mechanisms are incompletely defined. Overproduction of the inflammatory mediator prostaglandin (PG) E-2 by COPD fibroblasts contributes to reduced repair function. Objectives: The present study determined if fibroblasts from subjects with COPD overproduce PGE(2) after stimulation with the inflammatory cytokines IL-1 beta and tumor necrosis factor-alpha, and further defined the mechanism for overproduction. Methods: Fibroblasts were isolated from parenchymal tissue obtained from smokers with and without COPD undergoing lung surgery. PGE(2), cyclooxygenases (COX), and miR-146a in these cells were evaluated by in vitro studies. Measurements and Main Results: After stimulation with inflammatory cytokines, COPD fibroblasts produced 2.7-fold more PGE(2) compared with controls with similar smoking history. The increase in PGE(2) depended on induction of COX-2, which increased to a greater degree in fibroblasts from subjects with COPD. Cytokines also induced microRNA miR-146a expression in both fibroblasts, but significantly less in COPD fibroblasts. miR-146a caused degradation of COX-2 mRNA; reduced expression prolonged COX-2 mRNA half-life in fibroblasts from subjects with COPD. Cytokine-stimulated PGE(2) production and miR-146a expression in cultured fibroblasts correlated with clinical severity assessed by expiratory airflow and diffusion capacity. Conclusions: miR-146a seems to play a pathogenetic role in the abnormal inflammatory response in COPD. Increased half-life of inflammatory mRNAs is a mechanism of abnormal inflammation in this disease.