法尼基二磷酸合酶在转化生长因子β1诱导气道上皮细胞间质转化中的作用及机制研究

Bronchiolitis obliterans syndrome (BOS) characterised by small-airway fibrosis is the predominant factor limiting long-term survival after lung transplant. Epithelial-mesenchymal transition (EMT) plays an important role in the development of BOS. Our preliminary data have demonstrated that transforming growth factor β1 (TGF-β1) protein level was increased in bronchoalveolar lavage fluid (BALF) from lung transplant recipients with BOS, and the protein level of farnesyl diphosphate synthase(FPPS) and EMT marker Vimentin were upregulated, while EMT marker E-cadherin was downreguated in the allograft airway epithelial cells from lung transplant recipients with BOS. In addition, FPPS inhibitor Zoledronate could inhibit the in vitro airway epithelial cell proliferation and migration induced by TGF-β1. Based on these data we propose that FPPS and TGF-β1 may form a positive feedback loop to amplify and promote the EMT effect induced by TGF-β1, which result in allograft middle and small airway fibrosis and airway remodeling post-transplantation, finally leading to BOS. In the present study, we firstly measure the expression level of FPPS and EMT markers in lung samples from recipients with BOS and analyze the correlation between FPPS and EMT markers; we then investigate whether FPPS is involved in TGF-β1-induced EMT in airway epithelial cell and the underlying molecular mechanism by using human airway epithelial cell line and rat lung transplant model with BOS. Our study may provide theoretical evidence that therapeutic modulation of FPPS and TGF-β1 signaling may be an effective strategy to prevent and treat lung transplant recipient with BOS.

闭塞性细支气管炎（BOS）是制约肺移植术后患者生存的主要因素，气道上皮间质转化（EMT）在BOS的发生发展中发挥重要作用。我们前期研究结果显示，肺移植术后合并BOS患者肺泡灌洗液中TGF-β升高，同时气道上皮细胞法尼基二磷酸合酶（FPPS）表达水平升高，EMT标记物E-cadherin表达降低，Vimentin表达升高；FPPS抑制剂能够抑制TGF-β1诱导的上皮细胞增殖和迁移。我们推测FPPS可能通过与TGF-β1形成正反馈，放大并促进TGF-β1诱导EMT效应，从而引起移植肺中小气道纤维化和气道重构，最终导致肺移植术后BOS的发生。本研究拟通过对肺移植术后BOS患者肺组织中FPPS和EMT标记物进行关联分析，采用人气道上皮细胞和大鼠肺移植BOS模型，探讨FPPS在TGF-β1诱导的移植肺气道上皮EMT转化过程中的作用及可能机制，以期为临床预防和治疗肺移植术后BOS提供理论指导和帮助。

闭塞性细支气管炎（BOS）是制约肺移植术后患者生存的主要因素，气道上皮间质转化（EMT）在BOS的发生发展中发挥重要作用。我们的前期研究显示，肺移植术后合并BOS患者肺泡灌洗液中TGF-β升高，同时上皮细胞法尼基二磷酸合酶（FPPS）表达水平升高，EMT标记物E-cadherin表达降低，Vimentin表达升高；FPPS抑制剂能够抑制TGF-β1诱导的上皮细胞增殖、黏附和迁移。我们推测FPPS可能通过与TGF-β1形成正反馈，放大并促进TGF-β1诱导的EMT效应，从而引起移植肺中小气道纤维化和气道重构，最终导致肺移植术后BOS的发生。本研究拟通过对肺移植术后BOS患者肺组织中FPPS和EMT标记物进行关联分析，采用人气道上皮细胞和大鼠肺移植BOS模型，研究结果表明FPPS通过p38 MAPK途径介导了TGF-β1诱导气道上皮细胞发生的EMT。本研究为临床预防和治疗肺移植术后BOS提供理论指导和帮助。