TGF-β1/Smads信号通路在食管支架术后良性再狭窄中的作用及机制研究

Although stent placement is effective in the treatment of benign or malignant esophageal strictures, restenosis secondary to tissue hyperplasia after stent placement remains a tough problem. Previous studies have shown the activation and proliferation of esophageal fibroblasts plays the most important role in the formation of benign esophageal restenosis after stent placement, but its molecular mechanism is unclear. It is reported that TGF-β receptor kinase inhibitor could reduce the proliferation of esophageal fibroblasts. Our preliminary experiment demonstrated that the levels of TGF-β1 and Smad2 were significantly increased in the hyperplastic tissues after esophageal stent placement. These findings indicate that TGF-β1/Smads signaling pathway may be involved in the formation of stent related esophageal restenosis. To validate this hypothesis, we aim to firstly investigate the effect of TGF-β1/Smads signaling on the proliferation of esophageal fibroblasts using intervention agents in vitro; secondly to detect the levels of key factors of TGF-β1/Smads signaling and its effect on fibroblast proliferation and collagen fiber deposition in the conditions of stent placement only or combined with TGF-β1 receptor inhibitor in vivo. Finally, these results may provide a new treatment strategy for the prevention of esophageal stent restenosis caused by tissue hyperplasia.

食管支架植入术是治疗食管良恶性狭窄的一种有效手段，但支架术后良性再狭窄是临床一个棘手难题。研究显示食管支架术后再狭窄最重要的细胞活动是食管成纤维细胞的活化增殖，但其活化增殖的分子病理机制尚不清楚。有报道发现应用TGF-β受体抑制剂可使食管支架术后成纤维细胞增殖减少，我们的预实验结果显示TGF-β1和Smad2 在食管支架术后增生组织中表达明显增加，提示TGF-β1/Smads信号通路可能参与支架术后再狭窄过程并发挥关键作用。为验证此推论，我们拟体外应用干预剂观察TGF-β1/Smads信号通路对食管成纤维细胞增殖影响，体内观测单纯食管支架术后和应用TGF-β1抑制剂后TGF-β1/Smads通路关键因子表达水平变化和对成纤维细胞增殖以及胶原纤维沉积的影响；从而明确TGF-β1/Smads信号通路在食管支架术后再狭窄中的作用及其机制，为临床防治食管支架术后良性再狭窄提供新的思路和方法。

食管支架植入术是治疗食管良恶性狭窄的一种有效手段，但支架术后良性再狭窄是临床一个棘手难题。研究显示食管支架术后再狭窄最重要的细胞活动是食管成纤维细胞的活化增殖， 但其活化增殖的分子病理机制尚不清楚。有报道发现应用TGF-β受体抑制剂可使食管支架术后成纤维细胞增殖减少，TGF-β1/Smads信号通路可能参与支架术后再狭窄过程并发挥关键作用。为验证此推论，我们成功在体外应用干预剂观察TGF-β1/Smads信号通路对食管成纤维细胞增殖影响，体内观测单纯食管支架术后和应用TGF-β1抑制剂后TGF-β1/Smads通路关键因子表达水平变化和对成纤维细胞增殖以及胶原纤维沉积的影响。我们的研究结果表明：（1）食管支架植入后的良性再狭窄与TGF-β1/Smads信号通路的高表达有关；（2）外源性TGF-β1抑制剂P144降低了大鼠成纤维细胞活化相关标志物的表达水平；（3）外源性TGF-β1抑制剂P144降低了大鼠支架植入后狭窄的严重程度；（4）TGF-β1抑制剂P144可通过TGF-β1/Smads信号通路降低大鼠食管成纤维细胞活化相关标志物的表达水平。 总的来说，本实验的结果明确了TGF-β1/Smads信号通路在食管支架术后再狭窄中的作用及其机制，为临床防治食管支架术后良性再狭窄提供新的思路和方法。