Epithelial origin of myofibroblasts during fibrosis in the lung.
Epithelial origin of myofibroblasts during fibrosis in the lung.
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DOI：
10.1513/pats.200601-004tk
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发表时间：
2006-06-01
期刊：
影响因子：
--
通讯作者：
Borok, Zea
中科院分区：
文献类型：
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作者：
Willis, Brigham C;duBois, Roland M;Borok, Zea
对肺纤维化潜在机制的了解仍然难以捉摸。曾经被认为主要是由慢性炎症引起的，现在很清楚，炎症和慢性纤维化，特别是在特发性肺纤维化/普通间质性肺炎等疾病中，通常是分离的，并且炎症对于诱发纤维化既不是必要的也不是充分的。肺纤维化的主要效应细胞——肌成纤维细胞的起源尚不清楚。已经假设了三个潜在来源。尽管驻留成纤维细胞的转化和循环骨髓源性祖细胞的分化可能发挥了一定作用，但肺泡上皮细胞（AEC）通过称为“上皮-间质转化”（EMT）的过程的可能贡献最近才得到考虑。 EMT 是上皮细胞失去细胞间附着、极性和上皮特异性标记、进行细胞骨架重塑并获得间充质表型的过程，在肾脏等成体组织的纤维发生中发挥着重要作用。本综述总结了支持 EMT 在肺纤维化发病机制中发挥核心作用的证据、EMT 在体外和体内 AEC 中的潜力以及转化生长因子-β1 在此过程中的作用，以及上皮驱动的纤维化对未来研究和治疗的影响。还讨论了涉及 EMT 的潜在途径。希望当前关于肺纤维化发生和相关途径的剖析范式的重大转变可能允许开发有针对性的干预措施，从而有可能逆转这一过程并改善异常修复和进行性纤维化的衰弱影响。
An understanding of the mechanisms underlying pulmonary fibrosis remains elusive. Once believed to result primarily from chronic inflammation, it is now clear that inflammation and chronic fibrosis, especially in diseases such as idiopathic pulmonary fibrosis/usual interstitial pneumonia, are often dissociated, and that inflammation is neither necessary nor sufficient to induce fibrosis. The origin of the primary effector cell of fibrosis in the lung, the myofibroblast, is not clearly established. Three potential sources have been hypothesized. Although conversion of resident fibroblasts and differentiation of circulating bone marrow-derived progenitors likely play a role, the possible contribution of alveolar epithelial cells (AECs), through a process termed "epithelial-mesenchymal transition" (EMT), has only recently received consideration. A process by which epithelial cells lose cell-cell attachment, polarity and epithelial-specific markers, undergo cytoskeletal remodeling, and gain a mesenchymal phenotype, EMT plays a prominent role in fibrogenesis in adult tissues such as the kidney. This review summarizes the evidence supporting a central role for EMT in the pathogenesis of lung fibrosis, the potential for EMT in AECs in vitro and in vivo and role of transforming growth factor-beta1 in this process, and the implications of epithelium-driven fibrosis on future research and treatment. Potential pathways involved in EMT are also discussed. It is hoped that a major shift in current paradigms regarding the genesis of pulmonary fibrosis and dissection of the relevant pathways may allow development of targeted interventions that could potentially reverse the process and ameliorate the debilitating effects of abnormal repair and progressive fibrosis.