RATIONALE: Persistent inflammation plays a major role in chronic obstructive pulmonary disease pathogenesis, but its mechanisms are incompletely defined. Over-production of the inflammatory mediator prostaglandin E2 by chronic obstructive pulmonary disease fibroblasts contributes to reduced repair function. OBJECTIVES: The present study determined if fibroblasts from chronic obstructive pulmonary disease subjects over-produce prostaglandin E2 following stimulation with the inflammatory cytokines, interleukin-1ss and tumor necrosis factor-alpha, and further defined the mechanism for over-production. METHODS: Fibroblasts were isolated from parenchymal tissue obtained from smokers with and without chronic obstructive pulmonary disease undergoing lung surgery. Prostaglandin E2, cyclooxygenases and miR-146a in these cells were evaluated by in vitro studies. MEASUREMENTS AND MAIN RESULTS: Following stimulation with inflammatory cytokines, chronic obstructive pulmonary disease fibroblasts produced 2.7-fold more prostaglandin E2 compared to controls with similar smoking history. The increase in prostaglandin E2 depended on induction of cyclooxygenase-2, which increased to a greater degree in fibroblasts from chronic obstructive pulmonary disease subjects. Cytokines also induced microRNA miR-146a expression in both fibroblasts, but significantly less in chronic obstructive pulmonary disease fibroblasts. MiR-146a caused degradation of cyclooxygenase-2 mRNA; reduced expression prolonged cyclooxygenase-2 mRNA half-life in fibroblasts from chronic obstructive pulmonary disease subjects. Cytokine stimulated prostaglandin E2 production and miR-146a expression in cultured fibroblasts correlated with clinical severity assessed by expiratory airflow and diffusion capacity. CONCLUSIONS: MiR-146a appears to play a pathogenetic role in the abnormal inflammatory response in chronic obstructive pulmonary disease. Increased half-life of inflammatory mRNAs is a mechanism of abnormal inflammation in this disease.
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