Reduced miR-146a increases prostaglandin E2 in chronic obstructive pulmonary disease fibroblasts

Tadashi Sato, Xiang-de Liu, Amy Nelson, Masanori Nakanishi, Nobuhiro Kanaji, Xingqi Wang, Miok Kim, Yingji Li, Jianhong Sun, Joel Michalski, Amol N Patil, Hesham E Basma, Olaf Holz, Helgo Magnussen, Stephen I. Rennard

Research output: Contribution to journalArticle

131 Scopus citations

Abstract

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 fromparenchymal 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 PGE2 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 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.

Original languageEnglish (US)
Pages (from-to)1020-1029
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume182
Issue number8
DOIs
StatePublished - Oct 15 2010

    Fingerprint

Keywords

  • Chronic obstructive pulmonary disease
  • Cyclooxygenase-2
  • Fibroblasts
  • Prostaglandin E
  • miR-146a

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Sato, T., Liu, X., Nelson, A., Nakanishi, M., Kanaji, N., Wang, X., Kim, M., Li, Y., Sun, J., Michalski, J., Patil, A. N., Basma, H. E., Holz, O., Magnussen, H., & Rennard, S. I. (2010). Reduced miR-146a increases prostaglandin E2 in chronic obstructive pulmonary disease fibroblasts. American Journal of Respiratory and Critical Care Medicine, 182(8), 1020-1029. https://doi.org/10.1164/rccm.201001-0055OC