间质转化在肺纤维化中的作用及分子机制

Role and molecular mechanism of mesenchymal transition in pulmonary fibrosis

关键词: 上皮间质转化(EMT)  内皮间质转化(EndMT)  巨噬间质转化(MMT)  TGF-β 信号通路  缺氧诱导因子-1α(HIF-1α)  协同网络

Keywords: epithelial mesenchymal transition(EMT)  endothelial mesenchymal transition(EndMT)  macrophage mesenchymal transition(MMT)  TGF-β signalling pathway  hypoxia-inducible factor-1α(HIF-1α)  collaborative network

摘 要: 肺纤维化是一种慢性间质性肺病,以细胞外基质异常沉积和胶原增生为特征,最终导致不可逆的肺瘢痕形成和呼吸衰竭。研究表明,间质转化在肺纤维化的发生发展中起重要作用。本文总结了上皮间质转化(EMT)、内皮间质转化(EndMT)、巨噬间质转化(MMT)在肺纤维化中的作用, 即: EMT 通过 TGF-/Smad、Wnt/β-catenin 和 Notch 信号通路抑制上皮标志物(E-钙黏蛋白),上调间质蛋白(α-SMA 和胶原);EndMT 受 TGF-β 信号主导,并与小窝蛋白-1(CAV-1)缺失及缺氧诱导因子-1α(HIF-1α)轴激活密切相关,导致内皮屏障破坏和胶原沉积;依赖 TGF-β/Smad 通路促使 M₂ 型巨噬细胞转分化为肌成纤维细胞,加速纤维化进程;三者通过共享 TGF-β 枢纽、转录因子网络(Snail/Zeb 等)及微环境交互形成自放大协同网络,共同推动肺纤维化进展。当前靶向治疗仍面临 TGF-β 抑制剂全身毒性、多靶点药物疗效有限等障碍,因此,深入解析间质转化的动态协同机制, 将为肺纤维化防治提供新思路。

Abstract: Pulmonary fibrosis is a chronic interstitial lung disease characterized by extracellular matrix abnormal deposition and collagen proliferation, which ultimately leads to irreversible lung scar formation and respiratory failure. Studies have shown that mesenchymal transition plays an important role in the occurrence and development of pulmonary fibrosis. This paper summarized the roles of epithelial mesenchymal transition (EMT), endothelial mesenchymal transition (EndMT), and macrophage mesenchymal transition (MMT)in pulmonary fibrosis: namely, EMT inhibits epithelial markers (E-cadherin) and up-regulates mesenchymal proteins (α-SMA, collagen)through TGF-β/Smad, Wnt/β-catenin and Notch pathways; EndMT is dominated by TGF-β signaling and closely associated with caveolin-1 (CAV-1) deficiency and hypoxia-inducible factor-1α (HIF-1α) axis activation, leading to endothelial barrier disruption and collagen deposition; relying on the TGF-β/Smad pathway promotes the differentiation of M₂-type macrophages into myofibroblasts, accelerating the fibrosis process. The three pathways form a selfamplifying synergistic network through sharing TGF-β hubs, transcription factor networks (Snail/Zeb, etc.), and microenvironmental interactions, that jointly promoting the progression of pulmonary fibrosis. Currently, targeted therapy still faces a few obstacles such as systemic toxicity of TGF-β inhibitors, limited efficacy of multi-targeted drugs etc. , therefore, in-depth analysis of the dynamic synergistic mechanism of mesenchymal transformation would provide some new idea for the prevention and treatment of pulmonary fibrosis.