甲珠防治肝纤维化基础及临床研究
摘要
肝纤维化是各种病因所致慢性肝病的共同病理过程,也是肝硬化发生的前奏和必经中间环节。其可逆性为临床防治肝硬化提供了良好契机,防治和逆转肝纤维化是延缓或阻止肝硬化发生的重要手段,为肝病患者延长寿命、提高生命质量提供了可能,是治疗各种慢性肝炎的远期目标。肝纤维化的防治和逆转已成为该领域国内外同行的研究热点。
目前的研究认为,肝纤维化的病理改变是细胞外基质(ECM)的增生和降解失衡所致,近年来研究显示许多中医方药对肝纤维化有很好的治疗效果,并已展示良好的应用前景。从祖国医学辩证,认为肝纤维化是由于气滞、血瘀、络阻所致,肝纤维化初期主要为气滞,进而血瘀,最后络阻,气机不畅,肝纤维化、肝硬化形成。甲珠为穿山甲的鳞片,主归肝经,具有软坚、通络、散结的功效,是历代医家治疗癥、瘕、集、聚的常用药,近来,被广泛用治肝硬化取得了较好的临床效果。
本实验利用CCl4建立急性肝损伤和慢性肝纤维化的实验鼠动物模型,造模两周后采用中药甲珠不同剂量灌胃,干预肝纤维化的形成,观察实验效果,探讨其抗肝纤维化的机制,结果发现甲珠通过提高机体对自由基的清除能力,保护肝细胞,改善肝功能,减少肝纤维化发生发展的始动因素,对治疗组各肝纤维化指标有明显改善;通过临床病例治疗观察,进一步证实甲珠对肝纤维化的有一定的防治作用。为临床甲珠抗肝纤维化提供了理论基础。
Hepatic fibrosis is the common pathological process that occurs as a result of a variety of most chronic liver diseases, and it is the pathogenesis and center bit of cirrhosis. Its reversibility can offer the chance to prevent and cure the cirrhosis in clinical practice. In the world a lot of scientists have send the focus in the reversibility and prevention and cure of liver fibrosis that can prevent or stop the process of cirrhosis. And it is possible to increase in life span and elevate the quality of life. So it is the long-term target to treat the most chronic hepatitis.
Up to now investigation reflect that the pathogenesis of the hepatic fibrosis is result from the imbalance of the proliferation and degradation of extracellular matrix (ECM). And in pathological condition the hepatic satellite cell (HSC) is the source that ECM was producted.The role of the process of fibrosis is the activation and proliferation of HSC, it is the central loop of the pathogenesis and development of the hepatic fibrosis. The one of the characteristics of the activited HSC is the expression ofα-SMA.α-SMA is the mark of the activited HSC. TGF-β1 is the strong stimulating factor of the activiting of HSC,and the primary cytokine of the process of the hepatic fibrosis, it plays the most effectiveness in the pathogenesis and development of hepatic fibrosis,it can advance HSC transforming to FSC, make ECM synthesis by stimulating FSC,inhibit the degradation of collagenase and matrix,stimulat the TIMP production, inhibit the activity of MMP and play the chemotaxis for FSC. In addition, the studies indicated that TGF-β1 can inhibit the expression of glu-cysteine joinase,enhance the damage of hepatic cell.and than TGF-β1 can also inhibit DNA synthesis and prevent the cell regeneration. Existent studies indicated that activation of TGFp-Smad signaling pathways is closely linked to occurrence and development of hepatic fibrosis and abnormal expression of Smads Plays an important role in occurrence and development of hepatic fibrosis. Hepatic fibrosis is predominantly characterized by excessive accumulation of extracellular matrix (ECM) components in the liver,caused by an imbalance between Synthesis and degradation of ECM.UP to now, no effective treatment of hepatic fibrosis is available for elinical use, in Particular, no method for enhancing degradation and resolution of these deposited ECM, and reversing hepatic fibrosis. we guess SOD-like activity and hydroxyl radical scavenging activity. Accordingly has relate of hepatic fibrosis. we guess Jiazhu can inhibit oxidative stress of kupffer cells and hasten recovery of hepatic fibrosis.
Many recent research indicated that lots of chinese traditional medicine had the effects on treating the hepatic fibrosis and appeared a long perspective.In according to the chinese traditonal medicine view, the hepatic fibrosis was thought that it was the result from air stagnant,blood stasis, collaterals lock. In the initial stage, hepatic fibrosis occure as a result from air stagnant at first step,and then blood stasis, and at last collaterals lock, functional activity of QI being not smooth. Pangolin Scale belong to the liver meridian, have the effect of the softening hard mass, dia-collaterals and eliminating stagnation.It is frequently used by a large number of doctors. Recently it was widely used in clinical practice for cirrhosis and shown a better effect. This experiment were divided into two parts (foundation experiment anf clinical trial),in foundation experiment the hepatic fibrosis model of rats was found by carbon tetrachloride ,the protective efffects of Jiazhu of different dose were observed for the experimental liver damage. Colchicine was used in control group. The influencing of Pangolin Scale on the liver function, pathology, hepatic oxidative stress states, hepatic tissue collagen accumulation, the activation of HSC and the expression of theα-SMA, TGF-β1, Smad3, were observed by using immunohistochemistry staining, RT-PCR, Western blot and other biochemical and (or) pathological techniques.Therefore,the synthetic therapeutic effects of the treatment on hepatic fibrosis by Jiazhu and the protective effects and mechanisms of Jiazhu on hepatic fibrosis were investigated in rats.That provide the theory proof for being widely used in clinical practice.
Results: Compared with the control group, Jiazhu (high-dose group, middle-dose group and low-dose group) can significantly decrease the ALT and AST level of hepatic fibrosis rats;and improve the ALB level (p<0.05). Compared with the control group and pretherapy, Jiazhu (high-dose group, middle-dose group and low-dose group) can significantly decrease the content of HA, LN, PCⅢand IVc in serum of fibrosis rats (p<0.01). The content of TGF-β1 decreased remarkably in Jiazhu group (p<0.01). Detection of level of Hyp、SOD、MDA in liver: Compared with the normal group,the level of Hyp、MDA of the model group was significantly increased, with the level of which in direct proportion to the severity of hepatic fibrosis.The level of Hyp、MDA were significantly lowered in treatment groups (p<0.05) Compared with the control group,the activity of SOD significantly decrease (p<0.05),but Jiazhu (high-dose group,middle-dose group and low-dose group) remarkably increase(p<0.05). Compared with the model group,the observation of pathohistology showed that the tissue damage and collagen have decreased significantly;The results of the immunohistochemistry showed that the Jiazhu could decrease the expression ofα-SMA、TGF-β1 and Smad3 significantly (p<0.05), and increase the gray scale remarkably (p<0.05).RT-PCR verified that the mRNA expression ofα-SMA、TGF-β1 and Smad3 of jiazhu group in liver tissue have decreased ramarkably compared with the control group.All results showed that Jiazhu group have the effect of reducing the index of hepatic fibrosis in serum and liver tissue,improving the pathological image of liver tissue,preventing and treating hepatic fibrosis.
In clinical trial, Jiazhu was orally administratered alone to patients for treating fibrosis. Compared with the control group ,the content of ALT and AST,HA,LN,PCⅢ,ⅣC,TGFβ-1,TIMP1 was decreased and the ALB was improved(P<0.05);the ultrasound conditon showed that the width of portal vein and splenic vein and the thickness of spleen have decreased significantly(P<0.05).Conclusion: Jiazhu can ameliorate every index of chronic liver disease, decrease the content of HA, LN, PCⅢ, IVc, TGF-β1, TIMP and decrease the width of portal vein and splenic vein and the thickness of spleen.So Jiazhu have the effect of reversing hepatic fibrosis.
Outcomes outlined above indicate that:
1. the Jiazhu ean protect liver from injury caused by CC14. could lessen liver cell injured, ameliorated liver function, therefore lightened the degree of hepatic fibrosis.
2. the Jiazhu can degrade the serum indicatrix of liver fibrosis and the content of HyP、MDA in the experimental hepatic fibrosis in rats. and raised the level of SOD. That to say, the anti hepatic fibrogenic mechanism maybe is concerned with anti-lipid peroxidation.
3. the Jiazhu could significantly decreaseα-SMA expression in liver of rats with experimental hepatic fibrosis,suggesting its preventive effects against liver fibrosis.
4. the Jiazhu could greatly reduce the expression levels of TGF-βl, Smad3, effectively deterring signal transformation of TGF-β/Smad,which is the molecular basis of effects of the Pangolin Scale on reducing hepatic fibrosis.
5. the Jiazhu can ameliorate every index of chronic liver disease, decreas the serum indicatrix of the content of HA,LN,PCⅢ,IVc,TGF-β1,TIMP1 and decrease the width of portal vein and splenic vein and the thickness of spleen.So Jiazhu have the effect of reversing hepatic fibrosis.
Significance and innovation of the study:
This study investigated the effect of Jiazhu on treating and reversing the experimental hepatic fibrosis in rats first time,demonstrated the potential mechanisms: Jiazhu can protect liver cells and ameliorate liver function by improving the capability of removing free radical; Jiazhu can interfere in the process of hepatic fibrosis by down-regulating the expression of TGF-β1 in liver tissue; Jiazhu can decrease hepatic sinusoid capillary vascularizing and ameliorate liver microcirculation by increasing the degradation of collagen. Jiazhu can improve the internal enviroment that HSC and others live in,reduce the activation of HSC,down-regulate the expression of TIMP-1 gene and improve the degradation of ECM.
目前的研究认为,肝纤维化的病理改变是细胞外基质(ECM)的增生和降解失衡所致,近年来研究显示许多中医方药对肝纤维化有很好的治疗效果,并已展示良好的应用前景。从祖国医学辩证,认为肝纤维化是由于气滞、血瘀、络阻所致,肝纤维化初期主要为气滞,进而血瘀,最后络阻,气机不畅,肝纤维化、肝硬化形成。甲珠为穿山甲的鳞片,主归肝经,具有软坚、通络、散结的功效,是历代医家治疗癥、瘕、集、聚的常用药,近来,被广泛用治肝硬化取得了较好的临床效果。
本实验利用CCl4建立急性肝损伤和慢性肝纤维化的实验鼠动物模型,造模两周后采用中药甲珠不同剂量灌胃,干预肝纤维化的形成,观察实验效果,探讨其抗肝纤维化的机制,结果发现甲珠通过提高机体对自由基的清除能力,保护肝细胞,改善肝功能,减少肝纤维化发生发展的始动因素,对治疗组各肝纤维化指标有明显改善;通过临床病例治疗观察,进一步证实甲珠对肝纤维化的有一定的防治作用。为临床甲珠抗肝纤维化提供了理论基础。
Hepatic fibrosis is the common pathological process that occurs as a result of a variety of most chronic liver diseases, and it is the pathogenesis and center bit of cirrhosis. Its reversibility can offer the chance to prevent and cure the cirrhosis in clinical practice. In the world a lot of scientists have send the focus in the reversibility and prevention and cure of liver fibrosis that can prevent or stop the process of cirrhosis. And it is possible to increase in life span and elevate the quality of life. So it is the long-term target to treat the most chronic hepatitis.
Up to now investigation reflect that the pathogenesis of the hepatic fibrosis is result from the imbalance of the proliferation and degradation of extracellular matrix (ECM). And in pathological condition the hepatic satellite cell (HSC) is the source that ECM was producted.The role of the process of fibrosis is the activation and proliferation of HSC, it is the central loop of the pathogenesis and development of the hepatic fibrosis. The one of the characteristics of the activited HSC is the expression ofα-SMA.α-SMA is the mark of the activited HSC. TGF-β1 is the strong stimulating factor of the activiting of HSC,and the primary cytokine of the process of the hepatic fibrosis, it plays the most effectiveness in the pathogenesis and development of hepatic fibrosis,it can advance HSC transforming to FSC, make ECM synthesis by stimulating FSC,inhibit the degradation of collagenase and matrix,stimulat the TIMP production, inhibit the activity of MMP and play the chemotaxis for FSC. In addition, the studies indicated that TGF-β1 can inhibit the expression of glu-cysteine joinase,enhance the damage of hepatic cell.and than TGF-β1 can also inhibit DNA synthesis and prevent the cell regeneration. Existent studies indicated that activation of TGFp-Smad signaling pathways is closely linked to occurrence and development of hepatic fibrosis and abnormal expression of Smads Plays an important role in occurrence and development of hepatic fibrosis. Hepatic fibrosis is predominantly characterized by excessive accumulation of extracellular matrix (ECM) components in the liver,caused by an imbalance between Synthesis and degradation of ECM.UP to now, no effective treatment of hepatic fibrosis is available for elinical use, in Particular, no method for enhancing degradation and resolution of these deposited ECM, and reversing hepatic fibrosis. we guess SOD-like activity and hydroxyl radical scavenging activity. Accordingly has relate of hepatic fibrosis. we guess Jiazhu can inhibit oxidative stress of kupffer cells and hasten recovery of hepatic fibrosis.
Many recent research indicated that lots of chinese traditional medicine had the effects on treating the hepatic fibrosis and appeared a long perspective.In according to the chinese traditonal medicine view, the hepatic fibrosis was thought that it was the result from air stagnant,blood stasis, collaterals lock. In the initial stage, hepatic fibrosis occure as a result from air stagnant at first step,and then blood stasis, and at last collaterals lock, functional activity of QI being not smooth. Pangolin Scale belong to the liver meridian, have the effect of the softening hard mass, dia-collaterals and eliminating stagnation.It is frequently used by a large number of doctors. Recently it was widely used in clinical practice for cirrhosis and shown a better effect. This experiment were divided into two parts (foundation experiment anf clinical trial),in foundation experiment the hepatic fibrosis model of rats was found by carbon tetrachloride ,the protective efffects of Jiazhu of different dose were observed for the experimental liver damage. Colchicine was used in control group. The influencing of Pangolin Scale on the liver function, pathology, hepatic oxidative stress states, hepatic tissue collagen accumulation, the activation of HSC and the expression of theα-SMA, TGF-β1, Smad3, were observed by using immunohistochemistry staining, RT-PCR, Western blot and other biochemical and (or) pathological techniques.Therefore,the synthetic therapeutic effects of the treatment on hepatic fibrosis by Jiazhu and the protective effects and mechanisms of Jiazhu on hepatic fibrosis were investigated in rats.That provide the theory proof for being widely used in clinical practice.
Results: Compared with the control group, Jiazhu (high-dose group, middle-dose group and low-dose group) can significantly decrease the ALT and AST level of hepatic fibrosis rats;and improve the ALB level (p<0.05). Compared with the control group and pretherapy, Jiazhu (high-dose group, middle-dose group and low-dose group) can significantly decrease the content of HA, LN, PCⅢand IVc in serum of fibrosis rats (p<0.01). The content of TGF-β1 decreased remarkably in Jiazhu group (p<0.01). Detection of level of Hyp、SOD、MDA in liver: Compared with the normal group,the level of Hyp、MDA of the model group was significantly increased, with the level of which in direct proportion to the severity of hepatic fibrosis.The level of Hyp、MDA were significantly lowered in treatment groups (p<0.05) Compared with the control group,the activity of SOD significantly decrease (p<0.05),but Jiazhu (high-dose group,middle-dose group and low-dose group) remarkably increase(p<0.05). Compared with the model group,the observation of pathohistology showed that the tissue damage and collagen have decreased significantly;The results of the immunohistochemistry showed that the Jiazhu could decrease the expression ofα-SMA、TGF-β1 and Smad3 significantly (p<0.05), and increase the gray scale remarkably (p<0.05).RT-PCR verified that the mRNA expression ofα-SMA、TGF-β1 and Smad3 of jiazhu group in liver tissue have decreased ramarkably compared with the control group.All results showed that Jiazhu group have the effect of reducing the index of hepatic fibrosis in serum and liver tissue,improving the pathological image of liver tissue,preventing and treating hepatic fibrosis.
In clinical trial, Jiazhu was orally administratered alone to patients for treating fibrosis. Compared with the control group ,the content of ALT and AST,HA,LN,PCⅢ,ⅣC,TGFβ-1,TIMP1 was decreased and the ALB was improved(P<0.05);the ultrasound conditon showed that the width of portal vein and splenic vein and the thickness of spleen have decreased significantly(P<0.05).Conclusion: Jiazhu can ameliorate every index of chronic liver disease, decrease the content of HA, LN, PCⅢ, IVc, TGF-β1, TIMP and decrease the width of portal vein and splenic vein and the thickness of spleen.So Jiazhu have the effect of reversing hepatic fibrosis.
Outcomes outlined above indicate that:
1. the Jiazhu ean protect liver from injury caused by CC14. could lessen liver cell injured, ameliorated liver function, therefore lightened the degree of hepatic fibrosis.
2. the Jiazhu can degrade the serum indicatrix of liver fibrosis and the content of HyP、MDA in the experimental hepatic fibrosis in rats. and raised the level of SOD. That to say, the anti hepatic fibrogenic mechanism maybe is concerned with anti-lipid peroxidation.
3. the Jiazhu could significantly decreaseα-SMA expression in liver of rats with experimental hepatic fibrosis,suggesting its preventive effects against liver fibrosis.
4. the Jiazhu could greatly reduce the expression levels of TGF-βl, Smad3, effectively deterring signal transformation of TGF-β/Smad,which is the molecular basis of effects of the Pangolin Scale on reducing hepatic fibrosis.
5. the Jiazhu can ameliorate every index of chronic liver disease, decreas the serum indicatrix of the content of HA,LN,PCⅢ,IVc,TGF-β1,TIMP1 and decrease the width of portal vein and splenic vein and the thickness of spleen.So Jiazhu have the effect of reversing hepatic fibrosis.
Significance and innovation of the study:
This study investigated the effect of Jiazhu on treating and reversing the experimental hepatic fibrosis in rats first time,demonstrated the potential mechanisms: Jiazhu can protect liver cells and ameliorate liver function by improving the capability of removing free radical; Jiazhu can interfere in the process of hepatic fibrosis by down-regulating the expression of TGF-β1 in liver tissue; Jiazhu can decrease hepatic sinusoid capillary vascularizing and ameliorate liver microcirculation by increasing the degradation of collagen. Jiazhu can improve the internal enviroment that HSC and others live in,reduce the activation of HSC,down-regulate the expression of TIMP-1 gene and improve the degradation of ECM.
引文
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