“病-方(效)-证”的研究实践与创新发展(三)——下瘀血汤治疗肝硬化的方证病理学基础探析

Research practice and innovative development of“disease⁃formula(effect)⁃syndrome”(Ⅲ)-Analysis on pathological basis of formula and syndrome of Xiayuxue Decoction in treatment of liver cirrhosis

基于肝炎后肝硬化气虚血瘀的核心病机,本课题组提出并论证了“血瘀为积之标,虚损为积之本”的肝硬化中医病机理论。采用不同功效中医古典方剂干预治疗肝硬化多种模型的研究表明,祛瘀的下瘀血汤干预肝硬化的作用特征是针对纤维结缔组织异常沉积、肝窦毛细血管化和肝血管异常新生。其作用机制包括下调金属蛋白酶组织抑制物表达,提高金属蛋白酶活性,促进病理性异常沉积胶原的降解,抑制肝星状细胞活化并诱导其凋亡,改善肝窦毛细血管化和抑制血管增生等,是下瘀血汤“治标”的作用特征。本文从“病-方(效)-证”相关的实验结果,解析了肝硬化血瘀病机的关键病理学基础主要为肝脏纤维结缔组织异常沉积和活化的星状细胞增殖,还包括胶原降解活性低下、肝窦内皮细胞开窗缺失、内皮下基底膜形成以及毛细血管化增加。以上为明确祛瘀方剂(如下瘀血汤)治疗现代疾病所针对的适应证(病理指征)提供了参考依据,并有助于促进临床转化应用。

Based on the core pathogenesis of qi deficiency and blood stasis in cirrhosis after hepatitis,the theory of traditional Chinese medicine(TCM)pathogenesis of liver cirrhosis“blood stasis is the superficial sign of lump accumulation,and intrinsic deficiency is the root cause of lump accumulation”is proposed and discussed.Studies using multiple liver cirrhosis models under intervention of classical TCM formulas with different function and effects have shown that the role of removing stasis by Xiayuxue Decoction against liver cirrhosis is characterized by targeting abnormal deposition of fibrous connective tissue,hepatic sinus capillarization and abnormal angiogenesis in the liver.The mechanism of Xiayuxue Decoction includes downregulating the expression of tissue inhibitors of metalloproteinases,increasing the activities of matrix metalloproteinases,promoting the degradation of pathological deposited collagens,inhibiting the activation of hepatic stellate cells and inducing their apoptosis,improving the hepatic sinus capillarization and inhibiting angiogenesis,which are its charcteristics of“treating symptoms”.Analyzing the experimental results related to“disease-formula(effect)-syndrome”reveals that the key pathological basis of the blood stasis in liver cirrhosis is mainly abnormal deposition of liver fibrous connective tissue and proliferation of activated stellate cells,low collagen degradation activity,lack of liver sinusoidal endothelial cell fenestration and formation of subendothelial basement membrane,and increased capillarization.The above provides a reference for clarifying the disease indications(pathological indications)targeted by stasis-dispelling formulas(such as Xiayuxue Decoction),and helps to promote clinical translational application.