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

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

Author information

1
Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-5910, USA.

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 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.

PMID:
20522791
PMCID:
PMC2970844
DOI:
10.1164/rccm.201001-0055OC
[Indexed for MEDLINE]
Free PMC Article

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