肝纤维化恢复期Kuffer cell对HSC凋亡的调控作用及信号转导机制研究
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摘要
肝纤维化是肝脏对慢性损伤的一种修复反应,是一种渐进的病理过程,以细胞外基质(extracellular matrix,ECM)增生为特征。近年来的研究表明,相对进展期的肝纤维化在去除了损伤因素后是可逆的,而在肝纤维化逆转这一过程中起关键作用的是肝星状细胞(hepatic stellate cell,HSC)的凋亡,因此,诱导肝星状细胞凋亡成为阻止肝纤维化进程的途径之一。研究显示在肝纤维化形成及恢复阶段,枯否细胞(kupffer cell,KC)发挥了双刃剑的作用。在肝纤维化进展期可促进HSC的激活,促进肝纤维化的形成;在肝纤维化恢复期,KC及活化的HSC可通过表达肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor related apoptosis inducingligand,TRAIL)及其他凋亡刺激因子从而促进HSC的凋亡,促进ECM的降解,从而抑制肝纤维化的形成。
鉴于HSC在肝纤维化发病中的重要作用及KC对HSC可能具有的双向调节作用,本研究拟选用CCl_4诱导的自愈性肝纤维化模型,研究KC在肝纤维化恢复期的促HSC凋亡作用,探讨其主要发挥作用的细胞因子TRAIL可能的HSC内信号传导通路以及来氟米特(leflunomide,Lef)对该通路的影响。研究内容主要包括以下三个部分:
1.确定肝纤维化病程的进展期和恢复期分期
在分别建立的8w、12w和16w由CCl_4诱导的自愈性肝纤维化模型上,经动态观察肝脏的病理组织学改变,结合能够敏感反应肝纤维化程度的血清学指标(HA,HA,LN,PCⅢ,CⅣ)和组织学指标—组织羟脯氨酸含量(Hydroxyproline,Hyp)的变化,初步确定CCl_4诱导大鼠肝纤维化模型的进展期和恢复期:进展期为模型12w,恢复期为12w模型恢复4w。
TUNEL和α-SMA双重染色显示,随着HSC的活化,HSC出现自发性凋亡,且凋亡的发生随激活进程而逐渐增加;而在肝纤维化恢复时期,随着恢复时间的延长,HSC的凋亡逐渐减少。提示由于HSC总数减少,HSC凋亡比例亦随之减少,表明活化HSC主要通过凋亡来终结其活化。RT-PCR结果表明,伴随活化HSC的凋亡,TIMP-1的mRNA的表达减少,而MMP_(13)的mRNA的表达随恢复时间的延长没有明显改变,始终维持在一个较高的水平。提示TIMPs表达水平的下降,解除了其对MMPs的抑制作用,使MMPs的活性增加,胶原分解增加,促使已形成的ECM降解,从而逆转肝纤维化。
2.探讨肝纤维化恢复期TRAIL的HSC内信号转导通路
TRAIL是肿瘤坏死因子家族成员中继肿瘤坏死因子(tumor necrosis factor,TNF)、FasL之后发现的第三个凋亡分子,其与细胞膜TRAIL受体结合从而发挥生物学作用。现已发现5种TRAIL受体,其中TRAIL-R1/DR4与TRAIL-R2/DR5含有死亡域,与TRAIL结合可诱导细胞凋亡。TRAIL-R3/DcR1、TRAIL-R3/DcR2及OGP不含死亡域,与TRAIL结合不能诱导细胞凋亡。同时人肝细胞表面几乎不表达TRAIL-R2/DR5受体,因此,TRAIL选择性诱导HSC凋亡的作用使其在肝纤维化的治疗中具有广阔的应用前景。
本研究采用Western-blot检测肝纤维化不同时期KC中TRAIL及HSC中TRAIL-R的表达及α-SMA和TRAIL-R2免疫荧光双染结果发现,活化的HSC表达DR4和DR5,静止的HSC表达DcR1和DcR2。将不同时期HSC和KC共培养发现,KC通过TRAIL经DR5诱导共培养体系中HSC的凋亡,且活化的HSC对TRAIL介导的凋亡更加敏感。将外源性寡聚化的FLAG-TRAIL预处理恢复期的HSC发现,在肝纤维化恢复期TRAIL经线粒体通路诱导HSC凋亡。上述结果提示,在肝纤维化恢复期,KC可通过TRAIL经DR5死亡受体通过线粒体途径介导HSC的凋亡。
3.探讨肝纤维化恢复期Lef对HSC内TRAIL信号转导通路的影响
HSC的激活、增殖是肝纤维化发生的一个中心环节,然而诱导或促进激活的HSC凋亡可避免或减少HSC聚积,这也可能成为抗肝纤维化治疗的重要对策之一。本研究显示,Lef活性代谢物,A771726(0.01,0.1和1μmol/L)预处理可明显促进肝纤维化恢复期HSC的凋亡。进一步研究发现A771726通过下调c-FLIP及RIP的表达,活化凋亡发生的死亡受体通路及上调Bid的表达,激活线粒体通路来诱导活化的HSC凋亡。以上实验结果综合说明了诱导HSC凋亡是来氟米特在肝纤维化治疗中的又一个作用机制。
Hepatic fibrosis represent the consequences of a sustained wound healing response to chronic liver injury,characterized by excessive deposition of extracellular matrix (ECM) proteins.A wealth of evidence now indicated that this process was irreversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of activated hepatic stellate cell(HSC) by apoptosis.Therefore,modulation of apoptosis of activated HSC could be an important complementary pathway in preventing hepatic fibrosis.
Recent studies demonstrated that the double-edged sword of kupffer cell(KC) activity in hepatic fibrosis progression versus recovery.During fibrosis progression,it is believed that KC is likely to promote activation of HSC.In contrast,during recovery of hepatic fibrosis KC could also provoke apoptosis of HSC by the expression of TNF-related apoptosis-inducing ligand(known as TRAIL) and other apoptotic stimul. In this study,using widely studied models induced by parenchymal injury from carbon tetrachlodde(CCl_4) treatment to investigate the mechanisms and regulative effect of TRAIL secreted from KC on apoptosis of HSC in recovery from hepatic fibrosis and the effects of leflunomide(Lef) on this signal pathway.The main contents are divided into three sections,as follows:
1.Determin distinct phases(progression phase and recovery phase) of hepatic fibrosis In this section,following dynamic observation the change of pathologic histology, the levels of HA、LN、Ⅳ-C and PCⅢin serum and Hyp in liver,we definited that the model of progression and recovery of hepatic fibrosis was rats with CCl_4 12 week and 4 week spontaneous recovery after injecting CCl_4 12 week.
By dual staining with TUNEL andα-SMA,spontaneous apoptosis was observed in activation HSC.During recovery from fibrosis,with the number of HSC reduced,the proportion of HSC apoptosis decreased,suggesting that HSC cell numbers are controlled by apoptosis.It is well known that interstitial collagenase activity decreases during fibrotie liver injury,and this decrease occurs through the activity of TIMPs. Specially,the reduction in TIMPs levels is associated with an increase in eollagenase activity.Moreover,activated HSC may be an important source of these TIMPs in injured liver.We,therefore,quantified expression of rat interstitial collagens(MMP-13) in parallel with collagenase inhibitors TIMP-1 during recovery from hepatic fibrosis.In this study,an increase in procollagen-1,MMP13 and TIMP-1 mRNA expression was observed in rat liver homogenates of fibrosis model(treatment CCl_412 w).After 8 wk spontaneous recovery,procollagen-1 and TIMP-1 mRNA expression significantly decreased.In contrast,MMP-13 mRNA expression remained at levels comparable to fibrosis model(treatment CCl_412 w) and does not diminish in parallel with TIMP-1 throughout 4 wk recovery.Our date indicated that apoptosis of HSC not only eliminates the major source of collagen,but also the major source of TIMP-1,the inhibitor of matrix degradation.That leads to increased activity of MMP-13 interstitial collagenase, which is the primary mechanism of fibrosis resolution.
2.Investigation TRAIL-elicited signal transductions pathway in HSC during recovery from hepatic fibrosis.
Tumor necrosis factor related apoptosis-inducing ligand(TRAIL) was identified on the basis of sequence homology to other members of the TNF family.Currently,five TRAIL receptors belonging to the TNF-a receptor superfamily have been identified. Two of them,TRAIL-R1/DR4 and TRAIL-R2/DR5 contain death domains,signal apoptosis by using the adapter protein FADD,and induce apoptosis via a caspase-dependent process,whereas TRAIL-R3/DcR1 and TRAIL-R4/DcR2 act as putative decoy receptors and do not transmit the death signal.Furthermore, TRAIL-R1/DR4 and TRAIL-R2/DR5 were seldom expressed in surface of human hepatocytes.Accordingly,selective removal only activated and not quiescent HSC via TRAIL-induced apoptotic signaling would be a deal therapeutic approach to attenuate liver fibrosis.
Western-blot andα-SMA and TRAIL-R2/DR5 iimmunofluorescence dual tained results shown that,compared with control,activated HSC expressed TRAIL-R1/DR4 and TRAIL-R2/DR5.Moreover,in the coculture system of KC and HSC of distinct period,apoptosis of HSC was mediated by KC through TRAIL and activated HSC may be more susceptible to apoptotic stimuli than their quiescent counterparts.Exogenous oligomerization TRAIL interfered with HSC shown that,during recovery from hepatic fibrosis,TRAIL through chondrosome channel to induced apoptosis of activated HSC.
3.Investigation effect of Lef on TRAIL-elicited signal transductions pathway during recovery from hepatic fibrosis
Activation and proliferation of hepatic stellate cells are central in the development and progression of hepatic fibrosis,whereas their removal by apoptosis may contribute to the termination of this response.In this study,A771726(0.01,0.1和1μmol/L), leflunomide's metabolite,significantly increased apoptosis of HSC during recovery from hepatic fibrosis.Further research demonstrated that,A771726 could induce apoptosis of HSC in recovery,and the mechanism is by downregulation of c-FLIP and RIP,activation of apoptosis death receptor pathway,upregulation of Bid and amplification of the mitochondrial pathway.Collectively,priming apoptosis were novel insight into the mechanisms by which Lef may exert in hepatic fibrosis. metalloproteinase;cytokine;apoptosis;tumor necrosis factor-related apoptosis-inducing ligand;tumor necrosis factor-related apoptosis-inducing ligand receptor;leflunomide; A771726
鉴于HSC在肝纤维化发病中的重要作用及KC对HSC可能具有的双向调节作用,本研究拟选用CCl_4诱导的自愈性肝纤维化模型,研究KC在肝纤维化恢复期的促HSC凋亡作用,探讨其主要发挥作用的细胞因子TRAIL可能的HSC内信号传导通路以及来氟米特(leflunomide,Lef)对该通路的影响。研究内容主要包括以下三个部分:
1.确定肝纤维化病程的进展期和恢复期分期
在分别建立的8w、12w和16w由CCl_4诱导的自愈性肝纤维化模型上,经动态观察肝脏的病理组织学改变,结合能够敏感反应肝纤维化程度的血清学指标(HA,HA,LN,PCⅢ,CⅣ)和组织学指标—组织羟脯氨酸含量(Hydroxyproline,Hyp)的变化,初步确定CCl_4诱导大鼠肝纤维化模型的进展期和恢复期:进展期为模型12w,恢复期为12w模型恢复4w。
TUNEL和α-SMA双重染色显示,随着HSC的活化,HSC出现自发性凋亡,且凋亡的发生随激活进程而逐渐增加;而在肝纤维化恢复时期,随着恢复时间的延长,HSC的凋亡逐渐减少。提示由于HSC总数减少,HSC凋亡比例亦随之减少,表明活化HSC主要通过凋亡来终结其活化。RT-PCR结果表明,伴随活化HSC的凋亡,TIMP-1的mRNA的表达减少,而MMP_(13)的mRNA的表达随恢复时间的延长没有明显改变,始终维持在一个较高的水平。提示TIMPs表达水平的下降,解除了其对MMPs的抑制作用,使MMPs的活性增加,胶原分解增加,促使已形成的ECM降解,从而逆转肝纤维化。
2.探讨肝纤维化恢复期TRAIL的HSC内信号转导通路
TRAIL是肿瘤坏死因子家族成员中继肿瘤坏死因子(tumor necrosis factor,TNF)、FasL之后发现的第三个凋亡分子,其与细胞膜TRAIL受体结合从而发挥生物学作用。现已发现5种TRAIL受体,其中TRAIL-R1/DR4与TRAIL-R2/DR5含有死亡域,与TRAIL结合可诱导细胞凋亡。TRAIL-R3/DcR1、TRAIL-R3/DcR2及OGP不含死亡域,与TRAIL结合不能诱导细胞凋亡。同时人肝细胞表面几乎不表达TRAIL-R2/DR5受体,因此,TRAIL选择性诱导HSC凋亡的作用使其在肝纤维化的治疗中具有广阔的应用前景。
本研究采用Western-blot检测肝纤维化不同时期KC中TRAIL及HSC中TRAIL-R的表达及α-SMA和TRAIL-R2免疫荧光双染结果发现,活化的HSC表达DR4和DR5,静止的HSC表达DcR1和DcR2。将不同时期HSC和KC共培养发现,KC通过TRAIL经DR5诱导共培养体系中HSC的凋亡,且活化的HSC对TRAIL介导的凋亡更加敏感。将外源性寡聚化的FLAG-TRAIL预处理恢复期的HSC发现,在肝纤维化恢复期TRAIL经线粒体通路诱导HSC凋亡。上述结果提示,在肝纤维化恢复期,KC可通过TRAIL经DR5死亡受体通过线粒体途径介导HSC的凋亡。
3.探讨肝纤维化恢复期Lef对HSC内TRAIL信号转导通路的影响
HSC的激活、增殖是肝纤维化发生的一个中心环节,然而诱导或促进激活的HSC凋亡可避免或减少HSC聚积,这也可能成为抗肝纤维化治疗的重要对策之一。本研究显示,Lef活性代谢物,A771726(0.01,0.1和1μmol/L)预处理可明显促进肝纤维化恢复期HSC的凋亡。进一步研究发现A771726通过下调c-FLIP及RIP的表达,活化凋亡发生的死亡受体通路及上调Bid的表达,激活线粒体通路来诱导活化的HSC凋亡。以上实验结果综合说明了诱导HSC凋亡是来氟米特在肝纤维化治疗中的又一个作用机制。
Hepatic fibrosis represent the consequences of a sustained wound healing response to chronic liver injury,characterized by excessive deposition of extracellular matrix (ECM) proteins.A wealth of evidence now indicated that this process was irreversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of activated hepatic stellate cell(HSC) by apoptosis.Therefore,modulation of apoptosis of activated HSC could be an important complementary pathway in preventing hepatic fibrosis.
Recent studies demonstrated that the double-edged sword of kupffer cell(KC) activity in hepatic fibrosis progression versus recovery.During fibrosis progression,it is believed that KC is likely to promote activation of HSC.In contrast,during recovery of hepatic fibrosis KC could also provoke apoptosis of HSC by the expression of TNF-related apoptosis-inducing ligand(known as TRAIL) and other apoptotic stimul. In this study,using widely studied models induced by parenchymal injury from carbon tetrachlodde(CCl_4) treatment to investigate the mechanisms and regulative effect of TRAIL secreted from KC on apoptosis of HSC in recovery from hepatic fibrosis and the effects of leflunomide(Lef) on this signal pathway.The main contents are divided into three sections,as follows:
1.Determin distinct phases(progression phase and recovery phase) of hepatic fibrosis In this section,following dynamic observation the change of pathologic histology, the levels of HA、LN、Ⅳ-C and PCⅢin serum and Hyp in liver,we definited that the model of progression and recovery of hepatic fibrosis was rats with CCl_4 12 week and 4 week spontaneous recovery after injecting CCl_4 12 week.
By dual staining with TUNEL andα-SMA,spontaneous apoptosis was observed in activation HSC.During recovery from fibrosis,with the number of HSC reduced,the proportion of HSC apoptosis decreased,suggesting that HSC cell numbers are controlled by apoptosis.It is well known that interstitial collagenase activity decreases during fibrotie liver injury,and this decrease occurs through the activity of TIMPs. Specially,the reduction in TIMPs levels is associated with an increase in eollagenase activity.Moreover,activated HSC may be an important source of these TIMPs in injured liver.We,therefore,quantified expression of rat interstitial collagens(MMP-13) in parallel with collagenase inhibitors TIMP-1 during recovery from hepatic fibrosis.In this study,an increase in procollagen-1,MMP13 and TIMP-1 mRNA expression was observed in rat liver homogenates of fibrosis model(treatment CCl_412 w).After 8 wk spontaneous recovery,procollagen-1 and TIMP-1 mRNA expression significantly decreased.In contrast,MMP-13 mRNA expression remained at levels comparable to fibrosis model(treatment CCl_412 w) and does not diminish in parallel with TIMP-1 throughout 4 wk recovery.Our date indicated that apoptosis of HSC not only eliminates the major source of collagen,but also the major source of TIMP-1,the inhibitor of matrix degradation.That leads to increased activity of MMP-13 interstitial collagenase, which is the primary mechanism of fibrosis resolution.
2.Investigation TRAIL-elicited signal transductions pathway in HSC during recovery from hepatic fibrosis.
Tumor necrosis factor related apoptosis-inducing ligand(TRAIL) was identified on the basis of sequence homology to other members of the TNF family.Currently,five TRAIL receptors belonging to the TNF-a receptor superfamily have been identified. Two of them,TRAIL-R1/DR4 and TRAIL-R2/DR5 contain death domains,signal apoptosis by using the adapter protein FADD,and induce apoptosis via a caspase-dependent process,whereas TRAIL-R3/DcR1 and TRAIL-R4/DcR2 act as putative decoy receptors and do not transmit the death signal.Furthermore, TRAIL-R1/DR4 and TRAIL-R2/DR5 were seldom expressed in surface of human hepatocytes.Accordingly,selective removal only activated and not quiescent HSC via TRAIL-induced apoptotic signaling would be a deal therapeutic approach to attenuate liver fibrosis.
Western-blot andα-SMA and TRAIL-R2/DR5 iimmunofluorescence dual tained results shown that,compared with control,activated HSC expressed TRAIL-R1/DR4 and TRAIL-R2/DR5.Moreover,in the coculture system of KC and HSC of distinct period,apoptosis of HSC was mediated by KC through TRAIL and activated HSC may be more susceptible to apoptotic stimuli than their quiescent counterparts.Exogenous oligomerization TRAIL interfered with HSC shown that,during recovery from hepatic fibrosis,TRAIL through chondrosome channel to induced apoptosis of activated HSC.
3.Investigation effect of Lef on TRAIL-elicited signal transductions pathway during recovery from hepatic fibrosis
Activation and proliferation of hepatic stellate cells are central in the development and progression of hepatic fibrosis,whereas their removal by apoptosis may contribute to the termination of this response.In this study,A771726(0.01,0.1和1μmol/L), leflunomide's metabolite,significantly increased apoptosis of HSC during recovery from hepatic fibrosis.Further research demonstrated that,A771726 could induce apoptosis of HSC in recovery,and the mechanism is by downregulation of c-FLIP and RIP,activation of apoptosis death receptor pathway,upregulation of Bid and amplification of the mitochondrial pathway.Collectively,priming apoptosis were novel insight into the mechanisms by which Lef may exert in hepatic fibrosis. metalloproteinase;cytokine;apoptosis;tumor necrosis factor-related apoptosis-inducing ligand;tumor necrosis factor-related apoptosis-inducing ligand receptor;leflunomide; A771726
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