Reduced miR-146a increases prostaglandin E₂in chronic obstructive pulmonary disease fibroblasts

Am J Respir Crit Care Med. 2010 Oct 15;182(8):1020-9. doi: 10.1164/rccm.201001-0055OC. Epub 2010 Jun 3.


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) E₂ by COPD fibroblasts contributes to reduced repair function.

Objectives: The present study determined if fibroblasts from subjects with COPD overproduce PGE₂ after stimulation with the inflammatory cytokines IL-1β and tumor necrosis factor-α, and further defined the mechanism for overproduction.

Methods: Fibroblasts were isolated from parenchymal tissue obtained from smokers with and without COPD undergoing lung surgery. PGE₂, 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 PGE₂ compared with controls with similar smoking history. The increase in PGE₂ 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 PGE₂ 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Case-Control Studies
  • Cells, Cultured
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism*
  • Female
  • Fibroblasts / immunology*
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology*
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / immunology*
  • Severity of Illness Index
  • Smoking / adverse effects


  • Biomarkers
  • MIRN146 microRNA, human
  • MicroRNAs
  • Cyclooxygenase 2
  • Dinoprostone