Reduced miR-146a Increases Prostaglandin E2 in Chronic Obstructive Pulmonary Disease Fibroblasts
Reduced miR-146a Increases Prostaglandin E2 in Chronic Obstructive Pulmonary Disease Fibroblasts
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DOI：
10.1164/rccm.201001-0055oc
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发表时间：
2010-10-15
影响因子：
24.7
通讯作者：
Rennard, Stephen I.
中科院分区：
文献类型：
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作者：
Sato, Tadashi;Liu, Xiangde;Rennard, Stephen I.
基本原理：持续性炎症在慢性阻塞性肺疾病（COPD）的发病中起重要作用，但其机制尚不完全清楚。COPD成纤维细胞过度产生炎症介质前列腺素（PG）E-2有助于降低修复功能。目的：本研究确定COPD受试者的成纤维细胞在用炎症细胞因子IL-1 β和肿瘤坏死因子-α刺激后是否过度产生PGE（2），并进一步确定过度产生的机制。方法：成纤维细胞从接受肺手术的患有和不患有COPD的吸烟者获得的实质组织中分离。通过体外研究评估了这些细胞中的PGE（2）、环氧化酶（考克斯）和miR-146 a。测量和主要结果：在用炎症细胞因子刺激后，COPD成纤维细胞产生的PGE（2）是具有相似吸烟史的对照组的2.7倍。PGE（2）的增加依赖于考克斯-2的诱导，而COX-2在COPD受试者的成纤维细胞中增加的程度更大。细胞因子也诱导microRNA miR-146 a在两种成纤维细胞中表达，但在COPD成纤维细胞中显著较少。miR-146 a导致考克斯-2 mRNA降解; COPD受试者成纤维细胞中表达减少延长了考克斯-2 mRNA半衰期。结论：miR-146 a可能在COPD的异常炎症反应中起致病作用。炎性mRNA的半衰期增加是这种疾病中异常炎症的机制。
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) E-2 by COPD fibroblasts contributes to reduced repair function.Objectives: The present study determined if fibroblasts from subjects with COPD overproduce PGE(2) after stimulation with the inflammatory cytokines IL-1 beta and tumor necrosis factor-alpha, and further defined the mechanism for overproduction.Methods: Fibroblasts were isolated from parenchymal 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 PGE(2) 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 PGE(2) 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.