白桦脂醇靶向调节TGF-β1/Smads通路在预防食管ESD术后狭窄中的作用及机制研究

Esophageal stricture is a common complication of endoscopic submucosal dissection (ESD) for the treatment of esophageal mucosal lesions, which seriously affects the quality of life of patients. Fibrosis is the main cause of esophageal stricture after ESD. It is of great significance to study the drugs could prevent esophageal fibrosis after ESD and their mechanisms.It’s reported that betulin can improve fibrosis of liver and kidney, but its effect on fibrosis after esophageal ESD has not been reported. TGF-β1/Smads signal is an important regulator of fibrosis, but it needs further confirmation that it is related to esophageal fibrosis. Our Preliminary animal experiment found that betulin can reduce the degree of esophageal fibrosis after ESD, relieve postoperative esophageal stenosis, and significantly inhibit the expression of TGF-β1/Smads signal. Therefore, a hypothesis is put forward: betulin can prevent esophageal fibrosis and stenosis after ESD, and this effect is partly achieved by targeting the TGF-β1/Smads signaling pathwa. In current study，we will further verify the effect of betulin and elucidate it’s mechanism by HE and Masson staining, immunohistochemistry, RT-PCR, Western Blot and Luciferase reporter gene technology from cell, in vitro wound contraction models, animal models and human specimens level. This study is expected to provide new ideas for the prevention of esophageal stricture after ESD.

食管狭窄是是食管黏膜病变内镜黏膜下剥离术(ESD)后的常见并发症，严重影响患者生活质量。纤维化是ESD术后食管狭窄的主要原因，预防食管纤维化的药物及其作用机制研究具有重要意义。白桦脂醇可改善多种脏器的纤维化，但其对食管纤维化的影响尚无报道。TGF-β1/Smads通路是纤维化过程的重要调控子，但其与食管ESD术后纤维化的相关性尚需证实。我们前期预实验发现TGF-β1通路的活化与ESD术后食管狭窄潜在相关，白桦脂醇可以减轻ESD术后食管纤维化和狭窄程度，同时显著抑制上述通路的表达。由此提出假说：白桦脂醇可预防ESD术后食管纤维化和狭窄，这一效应部分是通过靶向TGF-β1/Smads通路而实现的。本研究拟从细胞、体外创面收缩模型、动物模型及人体标本水平，采用形态学、分子生物学及荧光素酶报告基因技术等进一步验证白桦脂醇的功效及阐明其作用机制。研究结果将为ESD术后食管狭窄的预防提供新思路。

研究背景:食管狭窄是是食管黏膜病变内镜黏膜下剥离术(ESD)后的常见并发症，严重影响患者生活质量。纤维化是ESD术后食管狭窄的主要原因，预防食管纤维化的药物及其作用机制研究具有重要意义。白桦脂醇可改善多种脏器的纤维化，但其对食管纤维化的影响尚无报道。TGF-β1/Smads通路是纤维化过程的重要调控子，但其与食管ESD术后纤维化的相关性尚需证实。.研究内容：为验证以上相关性我们从细胞、动物模型及人体标本水平，采用形态学、分子生物学及荧光素酶报告基因技术等进一步研究白桦脂醇预防食管ESD术后狭窄和纤维化的功效及潜在作用机制。.研究结果及数据：（1）食管ESD术后患者标本中TGF-β1/ Smads信号通路高表达与术后食管纤维化及狭窄密切相关。（2）白桦脂醇可抑制人食管成纤维细胞增殖能力，促进细胞凋亡，降低成纤维细胞中TGF-β1/ Smads信号的表达水平及胶原的表达量。（3）食管ESD术后狭窄动物模型实验提示白桦脂醇可有效减轻食管ESD术后狭窄的程度，抑制组织TGF-β1/ Smads信号的活化及纤维化程度。（4）白桦脂醇可以有效抑制TGF-β1基因启动子的活化及TGF-β1/Smads信号通路的表达。.科学意义：研究提示白桦脂醇可以抑制TGF-β1通路的活化从而减轻ESD术后食管纤维化和狭窄程度，为食管ESD术后狭窄的预防提高新的思路。