从TGF-β1/Smad、MAPK信号通路及其交互调控角度探讨扶肝化纤汤抗肝纤维化的作用机制

Hepatic fibrosis (HF) is the common pathological basis of chronic liver disease,but there are HF may reverse recovery. TGF-β1/Smad, MAPK signaling pathway plays a crucial regulatory role in the development of HF occurred, and influence each other, interactive control. Therefore control the two pathways,   especially to find and control the key link in the process of interaction, is one of the important targets for prevention of HF. Liver spleen, Chinese hilling Rong wood is the classic theory of TCM,As a guide, we believe that the TCM pathogenesis of HF.key is " Deficiency of vital qi, poison accumulate and blood stasis", the key lies in the treatment of strengthening the spleen and replenishing qi, promoting blood circulation, Chinese hilling Rong wood,resistance and detoxification,With this theory as the instruction form formula Fugan Huaxian Decoction(FGHXD) has good clinical efficacy, Early research has shown that can significantly improve liver fibrous tissue hyperplasia, cut TGF-β1mRNA xpression.This study hypothesis FGHXD is by regulating the TGF-β1/Smad, MAPK signal pathways and their interactions targets and give play to the role of anti liver fibrosis. To this end, we set up animal models combined disease, using technology such as molecular biology, cell culture, from the experiments in vivo and in vitro studies TGF - beta 1 / Smad and MAPK pathways in HF interaction and targets, clear FG mechanism or the treatment of HF and the theoretical basis of liver spleen, explore " Liver spleen, Chinese hilling Rong wood " the principle of modern medicine.

肝纤维化(HF)是慢性肝病的共同病理基础，但HF有逆转可能，TGF-β1/Smad、MAPK信号通路在HF发生发展中起关键作用，且互相影响、交互调控。因此调控这两条通路，尤其是找到并调控两者交互作用的关键环节，是防治HF的重要靶点。肝病实脾、培土荣木是中医经典理论，以此为指导，我们认为HF的中医病机关键是“正虚毒蕴血瘀”，治疗重在培土荣木、行气活血、扶正解毒 ，以此立法的扶肝化纤汤疗效显著，前期研究显示能够明显改善肝纤维组织增生、下调TGF-β1mRNA的表达。我们推测扶肝化纤汤是通过调控TGF-β1/Smad、MAPK信号通路及其交互作用靶点，起到抗HF作用。为此，拟建立病证结合动物模型，运用分子生物学、细胞培养等技术，从体内外实验研究TGF-β1/Smad与MAPK通路在HF中的交互作用及靶点，明确扶肝化纤汤抗HF的机制及肝病实脾的理论基础，探讨“肝病实脾、培土荣木”的现代医学原理。

肝纤维化(HF)是慢性肝病的共同病理基础，但HF有逆转可能，TGF-β1/Smad、MAPK信号通路在HF发生发展中起关键作用，且互相影响、交互调控。因此调控这两条通路，尤其是找到并调控两者交互作用的关键环节，是防治HF的重要靶点。肝病实脾、培土荣木是中医经典理论，以此为指导，我们认为HF的中医病机关键是“正虚毒蕴血瘀”，治疗重在培土荣木、行气活血、扶正解毒 ，以此立法的扶肝化纤汤疗效显著，前期研究显示能够明显改善肝纤维组织增生、下调TGF-β1mRNA的表达。为此成功建立了病证结合动物模型，运用分子生物学、细胞培养等技术，从体内外实验研究TGF-β1/Smad与MAPK通路在HF中的交互作用及靶点，实验结果显示：体内实验研究表明扶肝化纤汤可以改善肝纤维化大鼠的病理学改变，上调TGF-β1、Smad3表达及其mRNA表达，下调Smad7表达及其mRNA表达，在P38通路、ERK1/2通路及JNK1/2通路中能够下调P-P38、P-P38/P38、P-ERK1/2，P-ERK/ERK、P-JNK1/2、P-JNK/JNK蛋白表达。体外实验结果显示扶肝化纤汤含药血清能抑制TGF-β1诱导的肝星状细胞的增殖活化，下调TGF-β1诱导的肝星状细胞内Imp7/Imp8、P-Smad2/3的蛋白表达，阻断Smad2/3/4复合物的形成，在对TGF-β1诱导的大鼠肝星状细胞TGF-β1/Smad信号通路中，扶肝化纤汤含药血清与Smad3阻断剂有协同作用。验证了扶肝化纤汤是通过调控TGF-β1/Smad、MAPK信号通路及其交互作用靶点，起到抗HF作用，明确了扶肝化纤汤抗HF的机制及肝病实脾的理论基础。通过本课题研究培养人才9人，其中教师1人，硕士研究生9人；目前完成毕业论文5篇，待完成4篇（2018级硕士研究生2名、2019级硕士研究生2名）。研究成果已在国内中文核心学术期刊发表3篇，部分文章还在投稿中，专利正在申请中。