肝窦内皮细胞损伤和表型改变在大鼠肝硬化门脉高压发生中的作用

目的：探讨肝窦内皮细胞（SECs）损伤和表型改变与大鼠肝硬化门脉高压的关系。 方法： 采用二甲基亚硝胺（DMN）4周12次腹腔注射复制大鼠肝硬化模型，分别于造模后1 d、2 d、3 d、1周、2周、4周、6周、8周作动态观察；肠系膜前静脉分支插管法测门脉压力（Ppv）；透射电镜观察肝组织超微结构；免疫组化观察肝窦壁CD44和Ⅷ因子相关抗原（vWF）表达；Northern blot检测肝组织内皮素-1（ET-1） mRNA和内皮型一氧化氮合酶（eNOS）mRNA 表达；Western blot检测肝组织eNOS表达；放射免疫法测定血清透明质酸（HA）和肝组织ET-1含量。 结果： DMN造模1 d后CD44染色明显弱于正常对照组（P<0.05），SECs窗孔减少，血清HA含量显著高于正常对照组(P<0.05)；DMN造模2 d后vWF阳性染色明显强于正常对照组(P<0.05)；DMN大鼠的Ppv与肝窦壁vWF表达量和血清HA含量呈显著正相关(P<0.05)；造模2 d和3 d时ET-1 mRNA表达强于正常对照组，ET-1含量轻度高于正常对照组；造模1 d、2 d和3 d时eNOS mRNA表达强于正常对照组，而eNOS一直呈低水平状态。 结论：SECs损伤和表型改变是DMN大鼠肝硬化门脉高压形成的病理基础之一；ET-1和NO产生的平衡失调，使肝内血流阻力增加，在门脉高压形成过程中起重要作用。     

肝纤维化病理过程中ZEB1和ZEB2的动态表达变化及意义

目的:观察慢性肝损伤致肝纤维化过程中上皮-间质转化(EMT)调节蛋白锌指E盒结合同源盒蛋白(ZEB)1和ZEB2的动态表达变化并探讨其调节机制。方法:雄性Wistar大鼠40只,随机分为正常对照组、2周、4周、6周和8周模型组,每组各8只,模型组按3 mL/kg体重的剂量皮下注射60%CCl₄,每隔3 d注射1次,处死大鼠后测定肝脏指数、血清丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)活性,观察肝组织病理改变;免疫组织化学法检测肝组织中ZEB1、ZEB2、E-钙黏蛋白(E-cadherin)和α-平滑肌肌动蛋白(α-SMA)的表达情况;real-time RT-PCR方法检测肝脏组织中ZEB1及ZEB2 mRNA的表达变化。结果:模型各组大鼠肝脏指数、血清ALT和AST活性显著高于正常对照组(P＜0.01),8周模型组肝纤维化明显;随着肝脏损伤逐渐加重,纤维化程度加深,E-cadherin蛋白的表达显著降低,α-SMA蛋白表达显著升高,ZEB1和ZEB2蛋白和mRNA表达量也逐渐增加,8周模型组肝组织中ZEB1和ZEB2蛋白(46.42±14.36和57.71±13.32)与mRNA(189.00±47.39和277.28±48.55)表达较正常组显著增加(P＜0.01)。结论:ZEB1和ZEB2蛋白及mRNA表达量随纤维化程度的加重而增加,提示EMT可能通过ZEB1和ZEB2参与肝纤维化的发生发展。     

肝纤维化时肝脏OPN和PAI-1的表达变化

目的:研究骨桥蛋白(OPN)及纤溶酶原激活物抑制物(PAI-1)的表达特征及其在肝纤维化时的变化。方法:采用二甲基亚硝胺制作大鼠肝纤维化模型,大鼠肝脏常规HE和天狼猩红染色,采用SABC法做免疫组织化学染色及Western blotting检测OPN和PAI-1蛋白表达,抽提肝组织总RNA,RT-PCR检测OPN mRNA表达。结果:正常大鼠肝组织OPN和PAI-1表达极弱,肝纤维化大鼠肝脏中OPN表达增强,阳性信号散在或弥漫性分布,主要见于小叶内中央静脉周围、纤维间隔内以及周围巨噬细胞胞浆、枯否氏细胞、汇管区的部分肝细胞、肝窦壁内皮细胞。PAI-1在肝纤维化大鼠肝组织汇管区、肝细胞变性坏死处,肝窦周Disse间隙及毗邻以上部位的肝细胞,组织纤维间隔处及其外周细胞亦见阳性染色。Western blotting检测正常大鼠肝脏OPN的蛋白表达极低,肝纤维化组OPN的蛋白表达较正常组显著增强(P0.01)。与正常组比,肝纤维化组PAI-1表达也显著增强。RT-PCR检测结果显示,正常大鼠肝脏OPN mRNA表达极低,肝纤维化大鼠肝脏OPN mRNA的表达明显增强(P0.05)。研究结果证明,肝纤维化时大鼠肝组织OPN及PAI-1的表达水平显著增高。结论:肝纤维化时大鼠肝组织OPN及PAI-1的表达水平显著增高,OPN可能会促进PAI-1的高表达,从而抑制ECM降解、加速肝纤维化进程。     

迪康胶囊抗大鼠肝纤维化作用机制的实验研究

目的通过迪康胶囊治疗不同剂量二甲基亚硝胺(DMN)诱导的肝纤维化大鼠,分离星状细胞检测胞浆CollagenⅢ、αSMA、Smad3、Smad7mRNA表达的变化,以期了解其在抗肝纤维化作用中的分子机制,为其抗肝纤维化提供证据。方法Wistar雄性大鼠共50只,分为病理1组、2组,治疗1组、2组,正常对照组。分别以不同剂量诱导形成肝纤维化模型并用迪康胶囊治疗。6周后,处死大鼠,分离各组大鼠肝星状细胞,进行体外培养,采用RTPCR方法测定各组大鼠星状细胞中胞浆信号蛋白CollagenⅢ、αSMA、Smad3、Smad7的mRNA的表达,以磷酸甘油醛脱氢酶(GAPDH)做内参,琼脂糖电泳后照相读取灰度,以扩增片段/GAPDH的比值为mRNA的相对含量进行比较。结果两组病理组星状细胞CollagenⅢ、αSMA和Smad3mRNA与正常对照组相比表达均增加(P<0.01),两组病理组之间无统计学差异;而Smad3与正常组相比则无统计学差异。迪康胶囊治疗后,CollagenⅢ、αSMA和Smad3表达均下降(P<0.05),而Smad7表达则明显增加(P<0.05)。结论迪康胶囊缓解DMN诱导的大鼠肝纤维化程度,使其胶原表达减少,星状细胞αSMA的表达降低,使星状细胞胞浆信号蛋白Smad3的mRNA表达降低,Smad7mRNA表达升高,说明迪康胶囊对不同剂量DMN诱导的肝纤维化均有不同程度的抗纤维化作用。     

PI3K/Akt信号通路及内质网应激在肝纤维化大鼠肝细胞凋亡中的作用

目的观察磷脂酰肌醇-3激酶/蛋白激酶(PI3K/Akt)信号通路及葡萄糖调节蛋白78(GRP78)、生长停滞及DNA损伤基因(CHOP/GADD153)在四氯化碳(CCl4)诱导的肝纤维化中的表达并探讨其可能的作用。方法将30只SD大鼠随机分为正常组、肝纤维化模型(皮下注射40%CCl4橄榄油溶液)4及8周组。HE染色法观察肝组织病理形态学;用real-time PCR技术检测肝脏内GRP78及CHOP mRNA的表达;用Western blot检测肝脏内PI3K/Akt信号通路中Akt1、磷酸化Akt1及内质网应激相关蛋白GRP78及CHOP的表达;用原位末端转移酶标记(TUNEL)检测细胞凋亡。结果与正常组大鼠比较,肝纤维化模型4及8周组大鼠肝脏内GRP78及CHOP mRNA和蛋白表达均明显升高(P0.05),而肝脏内Akt1和磷酸化Akt1蛋白的表达则较正常大鼠显著降低(P0.05);与正常组大鼠比较,肝纤维化模型4及8周组大鼠肝细胞凋亡显著升高(P0.05)。结论 PI3K/Akt信号通路及内质网应激可能在肝纤维化大鼠肝细胞凋亡中发挥了重要作用。     

迪康胶囊对二甲基亚硝胺诱导的肝纤维化大鼠星状细胞TGFβⅡ型受体表达的影响

目的：探讨迪康胶囊对二甲基亚硝胺(DMN)诱导的肝纤维化大鼠星状细胞TGFβⅡ型受体表达的干扰作用。方法：采用流式细胞术检测大鼠星状细胞TGFβⅡ型受体。结果：以10μg/kg DMN注射3周后停止，再灌服迪康胶囊3周可使大鼠星状细胞TGFβⅡ型受体表达增加，而持续以5μg/kg DMN注射，灌服迪康胶囊对TGFβⅡ型受体无影响。结论：迪康胶囊对迪康胶囊对二甲基亚硝胺诱导的肝纤维化大鼠星状细胞TGFβⅡ型受体表达有一定增强作用。     

肝纤维化大鼠肝脏中内质网应激相关分子CHOP和TRB3的表达变化

 目的： 观察内质网应激相关分子CCAAT/增强子结合蛋白同源蛋白(CHOP）和Tribbles同源蛋白3（TRB3）在四氯化碳（CCl4）致大鼠肝纤维化过程中的表达变化,探讨其在肝纤维化过程中的可能作用。方法： 体重180～200　g的雄性Wistar大鼠随机分为正常4周组、正常8周组、肝纤维化4周组和肝纤维化8周组,肝纤维化组大鼠皮下注射40%CCl4制备肝纤维化模型,分别在4周和8周处死大鼠,观察肝组织病理改变,Western blotting检测肝脏活化转录因子6（ATF6）蛋白,免疫组化、Western blotting和real-time PCR分别检测肝脏CHOP和TRB3蛋白和mRNA表达变化,TUNEL法检测肝脏细胞凋亡。结果： 肝纤维化组大鼠肝脏可见假小叶形成,p90ATF6蛋白表达量较正常组明显减少（P<0.01）,p50ATF6蛋白表达量较正常组明显增加（P<0.01）,肝细胞胞浆CHOP和TRB3蛋白及mRNA表达量较正常组显著增加（P<0.01）,细胞凋亡率较正常组显著增加（P<0.01）。结论： 内质网应激相关分子CHOP和TRB3在CCl4致大鼠肝纤维化过程中蛋白及mRNA表达水平明显增加,其变化趋势与大鼠肝细胞凋亡率一致,提示内质网应激可能通过CHOP和TRB3促进肝细胞凋亡,参与肝纤维化发生发展。     

钙中性蛋白酶2及Bax在肝纤维化大鼠肝组织中的表达变化及意义

 目的：探讨钙中性蛋白酶2（calpain 2）及Bcl-2相关X蛋白(Bax)在肝纤维化过程中的表达变化及其在肝纤维化过程中的可能作用。方法:  雄性Wistar大鼠40只,随机分为正常对照4周、8周组和肝纤维化模型4周、8周组,每组各10只。肝纤维化组按3 mL/kg体重的剂量皮下注射40% CCl4植物油溶液,每隔3 d注射1次,造模时间分别为4周和8周;对照组大鼠皮下注射等量植物油溶液。采用TUNEL法检测肝组织中肝细胞凋亡情况;real-time PCR检测肝组织中calpain 2及bax mRNA的表达变化。免疫组织化学法及Western blotting检测肝组织中calpain 2及Bax蛋白的表达情况。 结果:  Real-time PCR检测发现肝纤维化4周和8周组大鼠肝组织中calpain 2及bax mRNA表达较相应的正常对照组显著增加。免疫组化及Western blotting检测显示肝纤维化4周组大鼠肝组织中calpain 2蛋白的表达与正常4周组比较无显著差异;随着肝纤维化程度的加重,肝纤维化8周时大鼠肝组织中calpain 2的表达显著增加;而肝组织中Bax的表达从肝纤维化4周时就显著增加,肝纤维化8周时达到高峰。此外,通过TUNEL法检测发现肝纤维化4周和8周组大鼠肝组织中肝细胞凋亡的数目较正常组大鼠显著增加。结论:  Calpain 2与Bax可能参与了肝纤维化的发生发展过程。     

PTEN在肝纤维化大鼠肝组织中的动态表达

目的： 探讨大鼠肝纤维化过程中肝组织PTEN的动态表达。方法: 采用胆总管结扎法建立大鼠肝纤维化模型,HE及Masson三色染色检测肝脏组织学变化,免疫组织化学染色、Western blotting及实时荧光定量PCR技术检测大鼠肝组织的PTEN蛋白及mRNA表达。结果: 大鼠肝纤维化模型成功建立,随着造模时间延长,肝纤维化程度逐渐加重,造模不同时间均可见不同程度的肝细胞变性坏死而导致正常肝细胞逐渐减少;免疫组织化学染色显示正常大鼠肝组织中PTEN广泛表达,主要表达于细胞浆,随着肝纤维化的进展,PTEN阳性表达细胞逐渐减少（P<0.01）;Western blotting及实时荧光定量PCR显示造模1周、2周、3周及4周不同时间大鼠纤维化肝组织中PTEN蛋白及mRNA表达均显著低于假手术组（P<0.01）,并随着肝纤维化的进展逐渐降低（P<0.01）。结论: 大鼠纤维化肝组织中PTEN蛋白及mRNA表达均随着肝纤维化的进展逐渐降低,其下降程度与肝纤维化程度一致。     

DcR3 对肝纤维化动物模型的影响

目的:研究DcR3 基因对肝纤维化大鼠的预防性治疗的作用。方法:SPF 级健康雄性Wistar 大鼠30 只,体重范围180 ~220 g,随机分为3 组,每组10 只,分别为正常对照组、DcR3 基因预防性治疗组(1% DMN+DcR3 组)、造模组(1%DMN 组)。采用1%DMN 诱导大鼠肝纤维化模型,腹腔注射DcR3 质粒进行预防性干预。分别采用HE 染色和Masson 染色观察肝组织病理情况;qRT-PCR 和Western blot 法检测DcR3、Fas、FasL、-SMA 和TGF-1 的mRNA 和蛋白表达水平。结果:与模型组相比,DcR3 预防治疗组大鼠肝组织炎性细胞浸润及胶原类物质沉积有所改善;DcR3 基因可显著降低肝纤维化大鼠Fas、FasL、 SMA 和TGF-1 mRNA 和蛋白表达水平,DcR3 基因预防性治疗组与对照组和造模组有显著性差异(P<0.05);同时DcR3 基因预防性治疗组DcR3 mRNA 和蛋白表达水平显著升高(P<0.05)。结论:DcR3 基因可有效防治大鼠肝纤维化,其作用机制可能是DcR3 通过降低肝脏炎症反应,减少胶原类物质沉积,抑制 SMA 和TGF-1 表达,从而抑制HSC 活化;下调Fas和FasL 表达,抑制Fas/ FasL 途径诱导的肝细胞凋亡。     

四氯化碳诱导肝纤维化早期大鼠肝窦内皮细胞及基底膜形态改变的动态研究

 目的：探讨四氯化碳诱导肝纤维化早期大鼠肝窦毛细血管化的形成过程。方法：清洁级雄性SD大鼠采用随机数字表法随机分为2组：正常对照组（N组,6只）和肝纤维化模型组（M组,32只）。M组大鼠腹腔注射50%四氯化碳蓖麻油混合液, N组大鼠腹腔注射生理盐水,剂量为2 mL/kg,每周2次,共4周。分别于造模第3天、1周、2周和4周处死大鼠,HE染色和Masson染色观察肝脏组织炎症及纤维化的改变,透射电镜观察肝窦内皮细胞（LSECs）窗孔与基底膜（BM）的改变,免疫组织化学检测LSECs表面标志物CD31及基底膜成分IV型胶原（Col IV）和层黏连蛋白（LN）的改变。结果：HE及Masson染色显示四氯化碳造模4周早期肝纤维化已形成。肝组织透射电镜显示四氯化碳造模第3天后开始出现LSECs窗孔直径变小及数目减少,随着造模时间的延长,LSECs失窗孔现象逐步严重,至第4周时局部内皮下可见连续的基底膜。免疫组化染色显示LSECs表面标志物CD31表达随着LSECs窗孔数目的减少而逐渐增强;基底膜成分Col IV于造模第2周时表达开始显著增强并随着造模时间延长表达逐渐增强,LN于造模第4周时表达开始显著增强。结论：肝纤维化早期大鼠局部肝组织可见典型的肝窦毛细血管化形成;肝窦壁内LN沉积是肝窦毛细血管化时形成连续基底膜的关键因素。     

瘦素及I和III型胶原蛋白在肝纤维化大鼠肝组织中的变化

 摘要： 目的 研究瘦素（Leptin）及I、 III型胶原蛋白及基因在肝纤维化模型组织中的动态表达水平。方法 四氯化碳（CCl4）皮下注射法制备肝纤维化模型,分别以Western blot及RT-PCR法检测Leptin及I、 III型胶原蛋白及基因在肝纤维化组织中的动态表达。结果 Leptin以及I、 III型胶原蛋白及基因在正常对照组肝脏中均有微量表达,CCl4注射2周后,三者的表达均开始增强,随着纤维化发展呈梯度增加。其mRNA表达水平在模型组明显高于正常组 (P<0.05);在肝纤维化过程中,Leptin与I型胶原(r=0.595,P=0.017)及Leptin与III型胶原(r=0.478,P=0.011) 的动态改变呈显著正相关。结论 Leptin的表达随着纤维化的程度加重而逐步增强,在肝纤维化过程中,Leptin可能参与了细胞外基质成分（ECM）的合成与降解。     

Phenotypical and morphological alterations to rat sinusoidal endothelial cells in arterialized livers after portal branch ligation

The hepatic sinusoids are preferentially supplied with portal venous blood and equipped with fenestrated endothelial cells that are distinct from capillary endothelial cells. We previously observed in rats that sinusoidal capillarization proceeded concurrently with arterial blood supply during hepatocarcinogenesis. This study aimed to clarify the inducing role of arterialization in sinusoidal capillarization by investigating phenotypical, morphological and functional alterations to sinusoidal endothelial cells (SECs) in arterialized rat livers induced by portal branch ligation. At one week, after massive hepatic necrosis following ligation, the livers were restored to their normal architecture without causing post-necrotic fibrosis. At 12-21 weeks, they exhibited a normal histology except for mild pericellular fibrosis which developed along sinusoids or between adjacent hepatocytes. SECs expressed factor VIII-related antigen and showed a decrease in the number of fenestrae and porosity, still lacking any basement membrane but further retaining the functional capacity for carmine dye uptake. Stellate cells, while occasionally associated with large amounts of collagen bundles, contained many lipid droplets and expressed no alpha-smooth muscle actin, indicating a quiescent property. Kupffer cells were commonly found within the sinusoids. The present results indicate that arterialization of the liver induces a partial (but not complete) transition of SECs into capillary-type endothelial cells, suggesting that arterialization might be one of the factors which induce sinusoidal capillarization in the development of hepatocellular carcinoma.     

Huangqi decoction inhibits apoptosis and fibrosis, but promotes Kupffer Cell activation in dimethylnitrosamine-induced rat liver fibrosis

ABSTRACT: BACKGROUND: Previously, Huangqi decoction (HQD) has been found to have a potential therapeutic effect on DMN-induced liver cirrhosis. Here, the mechanisms of HQD action against liver fibrosis were investigated in relation to hepatocyte apoptosis and hepatic inflammation regulation. METHODS: Liver fibrosis was induced by DMN administration for 2 or 4 weeks. Hepatocyte apoptosis and of Kupffer cells (KC) and hepatic stellate cells (HSC) interaction were investigated using confocal microscopy. The principle cytokines, fibrogenic proteins and apoptotic factors were investigated using western blot analysis. RESULTS: Compared with the DMN-water group, HQD showed decreased hepatocyte apoptosis and reduced expression of apoptotic effectors, cleaved-caspase-3, and fibrotic factors, such as smooth muscle alpha-actin (alpha-SMA), transforming growth factor beta-1 (TGF-beta1). However, the KC marker CD68 increased significantly in DMN-HQD liver. Confocal microscopy demonstrated widespread adhesion of KCs to HSCs in DMN-water and DMN-HQD rats liver. CONCLUSIONS: HQD exhibited positive protective effects against liver fibrosis; its mechanism of action was associated with protection from hepatocyte apoptosis and the promotion of CD68 expression in the devolopment of liver fibrosis to cirrhosis development.     

大鼠肝纤维化过程中4种肝脏细胞对纤溶系统的调节

目的:探讨在大鼠肝纤维化发展过程中,肝细胞、肝星状细胞(HSCs)、Kupffer细胞和内皮细胞(ECs)对纤溶系统的调节作用。方法:采用1周2次皮下注射50%CCl4、持续12周的方法制备大鼠慢性肝纤维化模型;将肝纤维化不同时期的4种肝脏细胞进行分离;采用Northern印迹法及Western印迹法分别测定大鼠各类肝脏细胞中尿激酶型纤溶酶原激活物(uPA)、以及它的抑制物(PAI-1)和受体(uPAR)的mRNA和蛋白表达。结果:Northern印迹法及Western印迹法分析均显示,在大鼠肝纤维化过程中,HSCs和ECs均为PAI-1、uPAR的主要产生细胞,相比之下,HSCs产生更多。结论:在大鼠肝纤维化发生发展过程中,HSCs和ECs对纤溶系统成分的产生起着重要的调节作用,而HSCs则是PAI-1、uPAR最主要的产生细胞。     

Antifibrotic effect of edaravone in rat liver cirrhosis induced by dimethylnitrosamine

Edaravone (EDA), a newly synthesized free radical scavenger, has shown excellent results in the treatment of stroke. An overproduction of reactive oxygen species (ROS) causing oxidative DNA damage has been accounted as a major factor causing liver injury and fibrosis. Therefore, we examined its effect of EDA in rat model of liver cirrhosis induced by dimethylnitrosamine (DMN). Ten rats (DMN-group) were injected intraperitoneally with DMN (10 μg/g body weight) alone and another ten rats (EDA-group) were injected intraperitoneally with EDA (10 mg/kg body weight) 2 h after being injected with DMN. Both groups underwent their injection regimen three times a week for 4 weeks, after which the rats were sacrificed and their liver tissue sections were stained with Azan–Mallory for quantitative analyses of fibrosis development, using soft imaging and a previously published scoring system. Additionally, these sections were immunohistochemically stained using an antibody against α-smooth muscle actin (α-SMA). The total-bililubin in the EDA-group was found to be lower than that in the DMN-group. Quantitive analysis of liver fibrosis showed that the fibrotic area of the EDA-group was significantly smaller than that of the DMN-group. Additionally, the number of α-SMA positive cells in the EDA-group were significantly lower than that in the DMN-group. This study showed that EDA reduces liver fibrosis in a rat of cirrhosis induced by DMN. These data suggest that the reduction of liver fibrosis by EDA may be induced by the suppression of activated hepatic stellate cells.     

Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats

Hepatocellular apoptosis, hepatic inflammation, and fibrosis are prominent features in chronic liver diseases. However, the linkage among these processes remains mechanistically unclear. In this study, we examined the apoptosis and activation of Kupffer cells (KCs) as well as their pathophysiological involvement in liver fibrosis process. Hepatic fibrosis was induced in rats by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4) treatment. KCs were isolated from normal rats and incubated with lipopolysaccharide (LPS) or from fibrotic rats. The KCs were stained immunohistochemically with anti-CD68 antibody, a biomarker for KC. The level of expression of CD68 was analyzed by western blot and real-time PCR methods. The apoptosis and pathophysiological involvement of KCs in the formation of liver fibrosis were studied using confocal microscopy. The mRNA and protein expression of CD68 were significantly increased in DMN- and CCL4-treated rats. Confocal microscopy analysis showed that CD68-positive KCs, but not α-smooth muscle actin (SMA)-positive cells, underwent apoptosis in the liver of DMN- and CCL4-treated rats. It was also revealed that the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and CD68-double-positive apoptotic KCs located in the portal or fibrotic septa area were situated next to hepatic stellate cells (HSCs). Tumor necrosis factor-α (TNF-α) and KC co-localized in the liver in the neighbor of HSCs. The double α-SMA- and collagen type I-positive cells predominantly existed in fibrotic septa, and those cells were co-localized clearly with CD68-positive cells. Interestingly, some CD68 and Col (1) double positive, but completely negative for α-SMA, were found in the portal areas and hepatic sinusoids; this phenomenon was also validated in primary isolated KCs after 6 h LPS exposure or fibrotic rats in vitro. These results show that KCs are associated with hepatocellular apoptosis, inflammation, and fibrosis process in a liver fibrosis models.