Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions
Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions
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DOI：
10.1002/path.4695
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发表时间：
2016-05-01
影响因子：
7.3
通讯作者：
Lopez-Cabrera, Manuel
中科院分区：
文献类型：
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作者：
Sandoval, Pilar;Jimenez-Heffernan, Jose A.;Lopez-Cabrera, Manuel
腹膜粘连（PA）是肠袢、实体器官和壁层腹膜之间形成的纤维化带，可能在手术、感染或子宫内膜异位症后出现。它们是一个严重的健康问题，没有有效的治疗方法。间皮细胞（MC）排列在腹膜腔中，并在病理条件下经历间皮-间充质转化（MMT），转化为肌成纤维细胞，其在腹膜纤维化组织中丰富。本研究的目的是研究腹膜MC是否经历有助于术后粘连形成的MMT。通过免疫组织化学、免疫荧光和定量RT-PCR对PA患者的活检进行分析。使用基于缺血钮扣的PA小鼠模型通过阻断转化生长因子-β（TGF-β）途径来调节MMT。研究粘连的严重程度和MMT相关标志物的表达。我们观察到肌成纤维细胞来源于肺动脉瘤患者的中膜下区MC的转化。此外，与同一患者远端正常腹膜组织相比，MMT相关标志物在粘连区失调。在动物实验中，阻断TGF-β导致与MC间充质转化相关的标记物的分子重编程，并显著降低粘连的严重程度。这些数据首次表明MMT参与PA发病机制。这一发现开辟了新的治疗策略，通过调节MMT与广泛的药理学药物干扰粘连形成。版权所有（c）2016大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Peritoneal adhesions (PAs) are fibrotic bands formed between bowel loops, solid organs, and the parietal peritoneum, which may appear following surgery, infection or endometriosis. They represent an important health problem with no effective treatment. Mesothelial cells (MCs) line the peritoneal cavity and undergo a mesothelial-to-mesenchymal transition (MMT) under pathological conditions, transforming into myofibroblasts, which are abundant in peritoneal fibrotic tissue. The aim of this study was to investigate if peritoneal MCs undergo a MMT contributing to the formation of post-surgical adhesions. Biopsies from patients with PAs were analysed by immunohistochemistry, immunofluorescence, and quantitative RT-PCR. A mouse model of PAs based on ischaemic buttons was used to modulate MMT by blocking the transforming growth factor-beta (TGF-) pathway. The severity of adhesions and MMT-related marker expression were studied. We observed myofibroblasts derived from the conversion of MCs in submesothelial areas of patients with PAs. In addition, MMT-related markers were dysregulated in adhesion zones when compared to distant normal peritoneal tissue of the same patient. In animal experiments, blockage of TGF- resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the adhesions. These data indicate for the first time that MMT is involved in PA pathogenesis. This finding opens new therapeutic strategies to interfere with adhesion formation by modulating MMT with a wide range of pharmacological agents. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.