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


OBJECTIVE
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.


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.
Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-5910, USA.
Tadashi
T
Sato
Xiangde
X
Liu
Amy
A
Nelson
Masanori
M
Nakanishi
Nobuhiro
N
Kanaji
Xingqi
X
Wang
Miok
M
Kim
Yingji
Y
Li
Jianhong
J
Sun
Joel
J
Michalski
Amol
A
Patil
Hesham
H
Basma
Olaf
O
Holz
Helgo
H
Magnussen
Stephen I
SI
Rennard
D015415:Biomarkers; D016022:Case-Control Studies; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology*; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects
D015415:Biomarkers; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D051546:Cyclooxygenase 2; D015232:Dinoprostone