“益肝康”单味药对肝星状细胞活化TGF-β1信号通路的影响及其有效成分分析
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摘要
肝纤维化(hepatic fibrosis，HF)是肝脏内细胞外基质(extra cellular matrix，ECM)弥漫性过度沉积性疾病，但无假小叶的形成。目前认为，肝纤维化是各种慢性肝病发展至肝硬化(liver cirrhosis，LC)的中间环节和前期病变。其发生机制主要是肝脏内ECM合成与降解失衡，表现为ECM在肝内的大量沉积。肝星状细胞(hepatic stellate cells，HSCs)的活化、增殖在此过程中发挥关键性作用。肝脏受损后释放多种细胞因子，如转化生长因子β1(transforming growth factor β1，TGF-β1、)、血小板衍生生长因子(platelet derived growth factor，PDGF)、肿瘤坏死因子a(tumor necrosis factor a，TNF-a)等，激活HSCs，使其转化为肌成纤维样细胞(myofibroblastic like cells，MFLCs)，胶原合成能力增加4-7倍，导致大量ECM沉积于肝脏，此为肝纤维化发生、发展的核心环节。抑制HSCs活化、增殖，诱导活化HSCs凋亡，促进胶原降解是防治肝纤维化的主要途径。
PDGF和TGF-β1在HSCs增殖和转化中分别担当重要角色。TGF-β1是目前发现最强有力的致纤维化细胞因子，PDGF是最强的促HSCs增殖因子。HSCs活化为MFLCs后可自分泌释放更多促纤维化细胞因子，形成正反馈放大式反应，HSCs活化在此放大环中处于中心地位。
TGF-β1是目前功能最明确、作用最强的促肝纤维化细胞因子，在促进HSCs胶原分泌中发挥主要作用。TGF-β1与HSCs表面高亲和力TGF-β受体(TβR)结合形成TGF-β1-TBR信号复合体后，进一步磷酸化下游信号—Smad蛋白家族，将信号转入胞内，启动HSCs的活化增殖。参与TGF-—信号细胞内传导的相关蛋白统称为Smad信号蛋白家族，为TGF-β下游信号传导分子的统称，分为三类：受体Smad(R-Smad)，其中的Smad 2、3是TGF-β1的下游受体Smad，与TGF-β1信号复合体结合后，核内移位，参与TGF-β1信号的细胞内传导。协同Smad(Co-Smad)，Smad 4，协助Smad 2、3进入细胞核，调节基因表达。抑制性Smad(I-Smad)，其中I-Smad 7可竞争性拮抗R-Smad 2、3与TGF-β1信号复合体的结合，阻断TGF-β1
Hepatic fibrosis (HF) is a kind of chronic disease with the characteristics of excessive extra cellular matrix (ECM) deposition throughout the liver, however, without the formation of pseudo-lobules. Now it is widely accepted that HF is the inevitable and preexisting stage for lots of chronic hepatic disease developing into liver cirrhosis (LC) eventually. The pathogenesis of HF is the disequilibrium between synthesis and decomposition of ECM, resulting in large quantity of ECM depositing in the liver. The activation and proliferation of hepatic stellate cells (HSCs) play a key role in the pathogenesis of HF. Many kinds of cytokines, such as transforming growth factor β1 (TGF-β1), platelet derived growth factor (PDGF) and tumor necrosis factor a (TNF-a), were released when livers were injured by various factors. HSCs were activated by such cytokines above, then the phenotype changed from quiescent HSCs to activated myofibroblastic like cells (MFLCs), with the increasing ability of collagen production to the extent of 4-7 times compared with the quiescent cells. Therefore, abundant of extra ECM which could not be decomposed deposited in the liver, which is the key step for fibrogenesis. Accordingly, to inhibit the activation and proliferation of HSCs, promote the apoptosis of MFLCs, and decompose the collagens might be the most effective strategy to treat HF.
Two kinds of cytokines—PDGF and TGF-β1, played an important role in the proliferation and phenotype transition of HSCs, respectively. TGF-β1 is the most potent cytokine of fibrogenesis known up to now, at the same time, PDGF is the factor which exerts the strongest effect on the proliferation of HSCs. More cytokines promoting fibrogenesis were released by autocrine when HSCs were activated to be MFLCs. Thus the proliferation and activation
PDGF和TGF-β1在HSCs增殖和转化中分别担当重要角色。TGF-β1是目前发现最强有力的致纤维化细胞因子，PDGF是最强的促HSCs增殖因子。HSCs活化为MFLCs后可自分泌释放更多促纤维化细胞因子，形成正反馈放大式反应，HSCs活化在此放大环中处于中心地位。
TGF-β1是目前功能最明确、作用最强的促肝纤维化细胞因子，在促进HSCs胶原分泌中发挥主要作用。TGF-β1与HSCs表面高亲和力TGF-β受体(TβR)结合形成TGF-β1-TBR信号复合体后，进一步磷酸化下游信号—Smad蛋白家族，将信号转入胞内，启动HSCs的活化增殖。参与TGF-—信号细胞内传导的相关蛋白统称为Smad信号蛋白家族，为TGF-β下游信号传导分子的统称，分为三类：受体Smad(R-Smad)，其中的Smad 2、3是TGF-β1的下游受体Smad，与TGF-β1信号复合体结合后，核内移位，参与TGF-β1信号的细胞内传导。协同Smad(Co-Smad)，Smad 4，协助Smad 2、3进入细胞核，调节基因表达。抑制性Smad(I-Smad)，其中I-Smad 7可竞争性拮抗R-Smad 2、3与TGF-β1信号复合体的结合，阻断TGF-β1
Hepatic fibrosis (HF) is a kind of chronic disease with the characteristics of excessive extra cellular matrix (ECM) deposition throughout the liver, however, without the formation of pseudo-lobules. Now it is widely accepted that HF is the inevitable and preexisting stage for lots of chronic hepatic disease developing into liver cirrhosis (LC) eventually. The pathogenesis of HF is the disequilibrium between synthesis and decomposition of ECM, resulting in large quantity of ECM depositing in the liver. The activation and proliferation of hepatic stellate cells (HSCs) play a key role in the pathogenesis of HF. Many kinds of cytokines, such as transforming growth factor β1 (TGF-β1), platelet derived growth factor (PDGF) and tumor necrosis factor a (TNF-a), were released when livers were injured by various factors. HSCs were activated by such cytokines above, then the phenotype changed from quiescent HSCs to activated myofibroblastic like cells (MFLCs), with the increasing ability of collagen production to the extent of 4-7 times compared with the quiescent cells. Therefore, abundant of extra ECM which could not be decomposed deposited in the liver, which is the key step for fibrogenesis. Accordingly, to inhibit the activation and proliferation of HSCs, promote the apoptosis of MFLCs, and decompose the collagens might be the most effective strategy to treat HF.
Two kinds of cytokines—PDGF and TGF-β1, played an important role in the proliferation and phenotype transition of HSCs, respectively. TGF-β1 is the most potent cytokine of fibrogenesis known up to now, at the same time, PDGF is the factor which exerts the strongest effect on the proliferation of HSCs. More cytokines promoting fibrogenesis were released by autocrine when HSCs were activated to be MFLCs. Thus the proliferation and activation
引文
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