The role of ambient air pollution is considered to be important in the development of chronic obstructive pulmonary disease (COPD), and pulmonary hypertension (PH) is a common clinical manifestation of COPD. However, many studies have mainly focused on the adverse health effects of a single air pollutant, ignoring the combined toxicity of multiple pollutants. In the present study, we co-exposed mice to coal-burning air pollutants (SO2, NO2 and PM2.5), and confirmed PH-like injury occurrence by airflow limitation, marked abnormal endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) expression, and histopathological and ultrastructural alteration. Global microRNA (miRNA) arrays identified three significantly changed miRNAs homologous with humans (miR-338-5p, miR-450b-3p and miR-142-5p), and we targeted miR-338-5p based on real-time reverse transcription-PCR (RT-PCR) validation. Furthermore, bioinformatic and dual-luciferase reporter gene analyses indicated that miR-338-5p bound to 3'-UTR of hypoxia-inducible factor 1α (HIF-1α) mRNA and down-regulation of miR-338-5p led to the increased expression of HIF-1α and its related gene four-and-a-half LIM (Lin-11, Isl-1 and Mec-3) domain 1 (Fhl-1) and contributed to PH. This study provides evidence for the role of miRNAs in PH through targeting HIF-1α/Fhl-1 pathway after air pollutants co-exposure and implies new insights into the molecular markers for COPD caused by air pollution.

中文翻译：

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MicroRNA-338-5p通过靶向HIF-1α/ Fhl-1途径调节由SO2，NO2和PM2.5共同暴露引起的肺动脉高压样损伤。

人们认为，环境空气污染的作用在慢性阻塞性肺疾病（COPD）的发展中很重要，而肺动脉高压（PH）是COPD的常见临床表现。然而，许多研究主要集中在单一空气污染物对健康的不利影响，而忽略了多种污染物的综合毒性。在本研究中，我们将小鼠与燃煤的空气污染物（SO2，NO2和PM2.5）共暴露，并通过气流受限，内皮素-1（ET-1）和内皮型硝酸盐的异常证实了PH样损伤的发生。氧化合酶（eNOS）的表达，以及组织病理学和超微结构改变。全球microRNA（miRNA）阵列鉴定出三种与人类同源的显着变化的miRNA（miR-338-5p，miR-450b-3p和miR-142-5p），我们基于实时逆转录PCR（RT-PCR）验证来靶向miR-338-5p。此外，生物信息学和双荧光素酶报告基因分析表明，miR-338-5p与缺氧诱导因子1α（HIF-1α）mRNA的3'-UTR结合，miR-338-5p的下调导致表达增加HIF-1α及其相关基因四个半LIM（Lin-11，Isl-1和Mec-3）结构域1（Fhl-1）的表达，并有助于PH的发生。这项研究通过空气污染物共同暴露后靶向HIF-1α/ Fhl-1途径，为miRNA在PH中的作用提供了证据，并暗示了由空气污染引起的COPD分子标记的新见解。缺氧诱导因子1α（HIF-1α）mRNA的-UTR和miR-338-5p的下调导致HIF-1α及其相关基因四分半LIM（Lin-11， Isl-1和Mec-3）域1（Fhl-1）并促进了PH。这项研究通过空气污染物共同暴露后靶向HIF-1α/ Fhl-1途径，为miRNA在PH中的作用提供了证据，并暗示了由空气污染引起的COPD分子标记的新见解。缺氧诱导因子1α（HIF-1α）mRNA的-UTR和miR-338-5p的下调导致HIF-1α及其相关基因四分半LIM（Lin-11， Isl-1和Mec-3）域1（Fhl-1）并促进了PH。这项研究通过空气污染物共同暴露后靶向HIF-1α/ Fhl-1途径，为miRNA在PH中的作用提供了证据，并暗示了由空气污染引起的COPD分子标记的新见解。