雌二醇对大鼠肝星状细胞TGF-β1、CTGF表达的影响

目的 探讨雌二醇对肝星状细胞(HSC)的影响及其可能的作用途径.方法 培养大鼠HSC,初次传代后,HSC随机分为4组,分别加入不同浓度的雌二醇,加药后72小时,噻唑蓝(MTT)法检测雌二醇对HSC增殖的影响;逆转录-聚合酶链式反应(RT-PCR)分析其对HSC的转化生长因子-β1(TGF-β1)、结缔组织生长因子(CTGF)的mRNA表达的影响;免疫细胞化学分析其对HSC的α-SMA蛋白的表达的影响.结果 MTT法发现雌二醇抑制HSC的增殖;RT-PCR分析雌二醇干预组HSC TGF-β1mRNA、CTGFmRNA的表达明显下降;免疫细胞化学分析雌二醇干预组HSC α-SMA蛋白表达明显下降;并且都随浓度增加抑制作用增强,差异有显著性(P＜0.05).结论 雌二醇具有抑制肝纤维化作用是因为:①可以抑制HSC的增殖、活化;②抑制了致纤维化生长因子TGF-β1及其下游信号CTGFmRNA表达.     

雌二醇对大鼠肝星状细胞MMP-2、TIMP-1表达的影响

目的探讨雌二醇对肝星状细胞（HSC）的影响及其可能的作用途径。方法培养大鼠HSC,初次传代后,HSC随机分为4组,分别加入不同浓度的雌二醇,噻唑蓝（MTT）法检测雌二醇对HSC增殖的影响;逆转录-聚合酶链式反应（RT—PCR）分析其对HSC的基质金属蛋白酶因子（MMP-2）、组织金属蛋白酶抑制剂（TIMP-1）的mRNA表达的影响;免疫细胞化学分析其对HSC的α—SMA蛋白的表达的影响。结果MTT法发现雌二醇抑制HSC的增殖,并且随浓度增加抑制作用增强,与阳性对照组比较雌二醇干预组HSCMMP-2mRNA表达增加（P〈0．01）,TIMP—1mRNA的表达下降（P〈0．01）,α-SMA蛋白表达明显下降（P〈0．05）。结论雌二醇具有抑制肝纤维化作用是因为：①可以抑制HSC的增殖、活化;②促进MMP-2mRNA的表达,抑制了TIMP-1mRNA的表达。     

银杏叶提取物对TGF-β1诱导的人Tenon's囊成纤维细胞增殖的影响及其机制的初步探讨

目的:观察银杏叶提取物(GBE)对转化生长因子-β1(TGF-β1)诱导的人Tenon's囊成纤维细胞(H TCFs)增殖的影响及可能机制.方法:体外培养HTCFs及鉴定;MTT法检测不同浓度的GBE(25、50、100、200 mg/L)对TGF-β1(2 ng/mL)诱导的HTCFs增殖的影响;流式细胞仪检测细胞周期;免疫细胞化学法观察α-平滑肌动蛋白(α-SMA)表达的情况.RT-PCR检测细胞结缔组织生长因子mRNA(CTGF mRNA)的表达.结果:TGF-β1可显著促进HTCFs的增殖,促进细胞由G0/G1期进入S期,上调α-SMA、CTGF在蛋白和mRNA水平的表达;GBE能够抑制TGF-β1的上述作用.结论:GBE具有抑制TGF-β1诱导的人Tenon's囊成纤维细胞增殖的作用,其机制可能是阻止细胞进入S期,下调α-SMA及CTGF的表达.     

肉苁蓉苯乙醇总苷对血小板衍生生长因子诱导的肝星状细胞增殖的影响及机制

目的探讨肉苁蓉苯乙醇总苷(CPh Gs)抑制血小板衍生生长因子-BB(rr PDGF-BB)介导的大鼠肝星状细胞(HSC)增殖活化作用及对PDGF/ERK_(1/2)信号通路表达的影响。方法培养HSC细胞,体外给予不同浓度(0、3.91、7.81、15.63、31.25、62.50、125.00、250.00和500.00 mg·L~(-1))的CPh Gs测定半数抑制率(IC50),选取25、50、75、100 mg·L~(-1)的CPh Gs,rr PDGF-BB刺激后,通过四甲基偶氮唑盐法(MTT)检测细胞的增殖;采用荧光定量PCR(RT-PCR)检测ERK_(1/2)、α-SMA、c-fos、c-jun和Collagen I mRNA的表达;进一步采用Western blot法检测CPh Gs对PDGF/ERK_(1/2)通路中ERK_(1/2)、P-ERK_(1/2)和Collagen I蛋白的表达。结果 (50~100)mg·L~(-1)的CPh Gs可以抑制rr PDGF-BB诱导的HSC的增殖(P<0.05);(25~100)mg·L~(-1)剂量组的CPh Gs均可抑制ERK_(1/2)、α-SMA、c-fos、c-jun和CollagenⅠmRNA水平的表达,并且明显抑制ERK_(1/2)、P-ERK_(1/2)和CollagenⅠ通路蛋白的表达。结论 CPh Gs的抗肝纤维化作用可能与其阻断PDGF/ERK_(1/2)通路进而阻断HSC的活化、增殖有关。     

鸢尾黄素对肝星状细胞外基质表达的影响

目的:研究鸢尾黄素对肝星状细胞的活化以及细胞外基质合成和降解的影响。方法:体外培养大鼠肝星状细胞株HSC-T6,通过荧光定量PCR法检测鸢尾黄素对肝星状细胞的Ⅰ型胶原、α-肌动球蛋白(α-SMA)、基质金属蛋白酶-13(MMP-13)以及基质金属蛋白酶-1抑制剂(TIMP-1)mRNA的表达的影响。结果:鸢尾黄素能显著抑制肝星状细胞中Ⅰ型胶原及活化标志α-SMA mRNA的表达,增强肝星状细胞中MMP-13 mRNA的表达,降低TIMP-1 mRNA的表达。结论:鸢尾黄素既可以有效地抑制肝星状细胞的活化,同时又能减少肝星状细胞胞外基质的合成以及增加胞外基质的降解,因而具有潜在的抗肝纤维化的作用。     

祛瘀化痰、散结消癥中药复方对细胞外基质降解调控系统及TGF-β_1 mRNA的影响

目的:研究祛瘀化痰、散结消癥中药复方对肾小球硬化中细胞外基质(ECM)降解调控系统及转化生长因子(TGF)-β1 mRNA的影响。方法:采用脂多糖刺激体外培养的大鼠肾小球系膜细胞,复制细胞增殖模型,用给药动物血清干预后,酶联免疫吸附法检测细胞上清液中基质金属蛋白酶(MMP-9)、基质金属蛋白酶抑制物(TIMP-1)的表达,计算MMP-9与TIMP-1比值,荧光定量PCR法检测细胞TGF-β1 mRNA表达。结果:各祛瘀化痰、散结消癥中药复方均能不同程度地抑制TIMP-1、上调MMP-9的表达,提高MMP-9与TIMP-1的比值,并下调细胞中TGF-β1 mRNA表达,其中以川芎+鳖甲+海藻组作用最明显。结论:祛瘀化痰、散结消癥中药复方能增强ECM降解,下调肾小球系膜细胞中TGF-β1 mRNA表达。     

生长抑制因子AcSDKP对转化生长因子β1促活化肝星状细胞合成和分泌细胞外基质的影响

目的:观察生长抑制因子N-乙酰基-丝氨酰-天门冬酰-赖氨酰-脯氨酸(AcSDKP)对转化生长因子β(1TGF-β1)促活化肝星状细胞(HSC)合成和分泌细胞外基质(ECM)的影响,探讨其抗纤维化作用机制。方法:大鼠HSC经原代分离培养活化后,分为空白对照组、TGF-β1组(5μg.L-1)、AcSDKP组(1nmol.L-1)、混合处理组(AcSDKP1nmol.L-1+TGF-β15μg.L-1),每组6个复孔,加入相应药物培养72h后,观察各组HSC形态学变化,检测其中Ⅰ型胶原(ColⅠ)mRNA、α平滑肌肌动蛋白(α-SMA)蛋白的表达及HSC上清液中玻璃酸(HA)的含量。结果:与空白对照组比较,TGF-β1组HSCColⅠmRNA表达、HA含量均明显升高(P<0.05),AcSDKP组ColⅠmRNA表达、HA含量、α-SMA蛋白表达均明显降低(P<0.05);与TGF-β1组比较,混合处理组ColⅠmRNA表达、HA含量、α-SMA蛋白表达均明显降低(P<0.05)。结论:AcSDKP可能通过抑制TGF-β1介导的活化HSC合成和分泌ECM,从而发挥其抗肝纤维化作用。     

瞬时感受器电位离子通道香草素受体亚家族4调控肝星状细胞活化增殖作用研究

目的探讨瞬时感受器电位离子通道香草素受体亚家族4(transient receptor potential vanilloid receptor 4,TRPV4)对肝星状细胞(hepatic stelate cell,HSC)活化增殖的作用及可能的作用机制。方法以含50%CCl4的花生油溶液(1m L·kg-1)皮下注射,建立大鼠肝纤维化模型。应用蛋白印迹等方法在体观察TRPV4及肌动蛋白α(α-smooth muscle actin,α-SMA)的蛋白表达变化。以转化生长因子-β1(transforming growth factor-β1,TGF-β1)(10μg·L-1)刺激肝星状细胞株(HSC-T6),离体观察TRPV4及α-SMA的蛋白表达变化。应用TRPV4非特异性抑制剂钌红(ruthenium red,Ru)及TRPV4-siRNA特异性沉默TRPV4,观察HSC-T6增殖及α-SMA、蛋白激酶B(protein kinase B,Akt/PKB)蛋白表达变化。结果肝纤维化组织与TGF-β1活化的HSC中TRPV4及α-SMA蛋白表达明显增加。阻断TRPV4可明显抑制HSC增殖,且α-SMA、Akt蛋白表达明显降低。结论 TRPV4参与调控HSC的活化增殖,调控Akt蛋白磷酸化。     

丹参酚酸B和姜黄素抑制大鼠肝星状细胞细胞外信号调节激酶的磷酸化

目的研究丹参酚酸B(SAB)和姜黄素(Cur)对大鼠肝星状细胞(HSC)增殖、活化和细胞外信号调节激酶(ERK)的作用。方法培养大鼠HSC-T6,使用SAB和Cur处理细胞,采用MTT法检测药物对细胞增殖的影响。收集裂解细胞并抽提细胞总蛋白,10%聚丙烯酰胺凝胶电泳分离蛋白,采用Western blot法检测药物对细胞表达α平滑肌肌动蛋白(α-SMA)、I型胶原、ERK和磷酸化ERK的影响。结果Cur剂量依赖性地抑制大鼠HSC的增殖和活化,SAB和Cur显著降低α-SMA的表达水平(P<0.01);SAB对I型胶原的分泌无影响(P>0.05)而Cur显著减少I型胶原的分泌(P<0.05)。SAB和Cur对ERK表达水平都没有显著影响(P>0.05),但是显著降低了磷酸化ERK的表达水平(P<0.01 vs.P<0.05)。结论SAB和Cur能够抑制HSC的增殖、活化和ERK的磷酸化。     

丹参酚酸B和姜黄素抑制大鼠肝星状细胞细胞外信号调节激酶的磷酸化

目的研究丹参酚酸B(SAB)和姜黄素(Cur)对大鼠肝星状细胞(HSC)增殖、活化和细胞外信号调节激酶(ERK)的作用。方法培养大鼠HSC-T6,使用SAB和Cur处理细胞,采用MTT法检测药物对细胞增殖的影响。收集裂解细胞并抽提细胞总蛋白,10%聚丙烯酰胺凝胶电泳分离蛋白,采用Western blot法检测药物对细胞表达α平滑肌肌动蛋白(α-SMA)、I型胶原、ERK和磷酸化ERK的影响。结果Cur剂量依赖性地抑制大鼠HSC的增殖和活化,SAB和Cur显著降低α-SMA的表达水平(P<0.01);SAB对I型胶原的分泌无影响(P>0.05)而Cur显著减少I型胶原的分泌(P<0.05)。SAB和Cur对ERK表达水平都没有显著影响(P>0.05),但是显著降低了磷酸化ERK的表达水平(P<0.01 vs.P<0.05)。结论SAB和Cur能够抑制HSC的增殖、活化和ERK的磷酸化。     

Paeoniae radix reduces PDGF-stimulated hepatic stellate cell migration

Hepatic stellate cells (HSCs) play a key role in the pathogenesis of liver fibrosis. In chronic liver injury, HSCs undergo transdifferentiation to an activated myofibroblastic phenotype and migrate to injured areas in response to chemotactic factors, producing extracellular matrix proteins such as collagen type I to repair the damage as well as overexpression of α-smooth muscle actin (α-SMA). Paeoniae Radix, the root of Paeonia lactiflora Pall, was investigated for PDGF-BB-induced HSC chemotaxis. Rat HSCs and LX-2, a human HSC cell line, were used for the in vitro experiments. Cell migration was analyzed by wound-healing and transwell assays. An ELISA and a Sircol collagen assay kit were used to detect the expressions of α-SMA and of collagen, respectively. Phosphorylations of mitogen-activated protein kinases, including ERK 1/2, p38, and JNK, were evaluated with immunoblotting. Results indicated that PDGF-BB increased migration as well as α-SMA and collagen expression in HSCs. Paeoniae Radix extracts and its active components, paeonol and 1,2,3,4,6-penta- O-galloyl- β-D-glucose (PGG), inhibited PDGF-BB-induced HSC migration and α-SMA and collagen expressions in a concentration-dependent manner. The inhibitory effects were associated with downregulation of PDGF receptor- α, ERK, p38, and JNK activation. Both paeonol and PGG participate in HSC migration, but via differential mechanisms.     

Anthocyanins isolated from the purple-fleshed sweet potato attenuate the proliferation of hepatic stellate cells by blocking the PDGF receptor

During the process of liver fibrosis, hepatic stellate cells (HSCs) play a critical role in the increased formation and reduced degradation of extracellular matrix in the liver. We investigated the anti-proliferative effects of an anthocyanin fraction (AF), isolated from the purple-fleshed sweet potato, on platelet-derived growth factor (PDGF)-BB-dependent signaling pathways in HSC-T6 cells. HSC proliferation plays a pivotal role in liver fibrogenesis. The AF suppressed HSC activation, including PDGF-induced proliferation and α-smooth muscle actin (α-SMA) expression. Additionally, AF inhibited PDGF-BB-induced Akt and ERK1/2 phosphorylation. AF inhibited the phosphorylation level of PDGF receptor-β (PDGFR-β) following PDGF-BB stimulation, providing a mechanism for the inhibition of AF-mediated kinase. These results suggest that AF suppresses HSC proliferation by blocking PDGFR-β signaling, inhibiting Akt and ERK1/2 activation and α-SMA expression.     

Docosahexaenoic acid attenuates carbon tetrachloride-induced hepatic fibrosis in rats

Fish oil containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has been reported to exert beneficial health effects, including hepatoprotection. However, the effect of DHA alone has not been well studied, and the mechanism is not fully understood. In the present study, we reported the protective effect of DHA on carbon tetrachloride (CCl₄) induced hepatic fibrosis. Compared with the control group, the CCl₄ group showed hepatic damage as evidenced by histological changes and elevation in serum transaminase activity, fibrosis, inflammation and oxidative stress levels. These pathophysiological changes were attenuated by chronic DHA supplementation. The anti-fibrotic effect of DHA was accompanied by reductions in gene and protein expression of α-smooth muscle actin (α-SMA), fibronectin, and collagen in the liver tissue. DHA also attenuated CCl₄-induced elevation of lipid peroxidation (LPO) and decrease of glutathione (GSH)/oxidized GSH (GSSG) ratio. The upregulated inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6 by CCl₄ were also ameliorated by DHA. Peroxisome proliferator-activated receptor (PPAR)-γ upregulation and type I and II receptors for transforming growth factor (TGF)-β (Tβ-RI and Tβ-RII) and platelet-derived growth factor (PDGF)-β receptor (PDGF-βR) downregulation on both mRNA and protein levels were observed by DHA treatment compared to CCl₄ group. Moreover, in vitro study showed that DHA inhibited HSC activation, being associated with elevating PPARγ level and reducing the phosphorylation levels of Smad2/3 and ERKs, which are downstream intermediates of TGFβ and PDGF receptors, respectively. Taken together, the hepatoprotective, anti-inflammatory and anti-fibrotic effects of DHA appeared to be multifactorial. Further, one of the mechanisms of the anti-fibrotic effect of chronic DHA supplementation is probably through PPARγ signaling to interrupt TGFβ/Smad and PDGF/ERK pathways in HSCs.     

吲哚-3-原醇对乙醛所致精密肝切片中星状细胞活化的影响

目的利用精密肝切片(PCLS)技术,研究吲哚-3-原醇(I3C)对乙醛活化肝星状细胞(HSCs)的作用及其机制。方法将200～800μmol.L-1的I3C及700μmol.L-1乙醛与PCLS共同孵育6h,免疫组化法分析肝切片中α-平滑肌肌动蛋白(α-SMA)表达,并检测培养液中谷胱甘肽S-转移酶(GST)和乳酸脱氢酶(LDH)活性、转化生长因子-β1(TGF-β1)含量、基质金属蛋白酶-1(MMP-1)及基质金属蛋白酶抑制物-1(TIMP-1)表达量及组织丙二醛(MDA)和羟脯氨酸(Hyp)含量。结果200～800μmol.L-1I3C可不同程度的减少乙醛激活的HSCs,并可明显降低乙醛升高的培养液中GST、LDH活性和肝组织中MDA和Hyp含量(P<0.05或P<0.01),呈良好的浓度依赖性。I3C给药组与乙醛对照组比较,培养液中TGF-β1含量降低(P<0.01),MMP-1/TIMP-1蛋白表达比值升高(P<0.01)。结论I3C能有效拮抗乙醛所致的HSCs活化,其机制与降低细胞氧化应激和促进基质胶原降解有关。     

姜黄素衍生物对原代大鼠肝星状细胞作用的体外研究

目的：观察姜黄素衍生物（Curc-OEG）抑制原代肝星状细胞（HSC）增殖、活化以及诱导其凋亡的作用,探讨其可能的作用机制。方法：采用IV型胶原酶、DNA酶消化SD雄性大鼠肝脏,percoll梯度离心得到纯化的肝星状细胞。细胞分离后1d分别加入0、6.25、12.5μg/mL的姜黄素衍生物,作用7d后用RT-PCR及Western blot检测细胞α-SMA、TGF-β1、Smad2的mRNA水平和蛋白表达量。活化的肝星状细胞在第14天分别加入0、6.25、12.5、25、50、75μg/mL的姜黄素衍生物,作用24h后RT-PCR检测凋亡基因Bax、Bcl-2的mRNA水平和纤维化相关基因TGF-β1、collagen I、NF-κB及TIMP-1的mRNA水平。结果：药物作用7d后,6.25μg/mL和12.5μg/mL浓度药物处理组与对照组相比,细胞数目分别减少了56%和86%。在12.5μg/mL浓度药物作用下,原代肝星状细胞α-SMA、TGF-β1及Smad2的mRNA表达水平分别下调83%、85%及75%,蛋白表达水平分别下调94%、92%及73%（P〈0.05）。25μg/mL浓度药物作用24h后,细胞凋亡明显。在50μg/mL浓度药物作用下,活化的肝星状细胞Bax的mRNA表达水平上调约2.3倍,Bcl-2的mRNA表达水平下调约5.6倍;TGF-β1、collagen I、NF-κB及TIMP-1的mRNA表达水平分别下调90%、83%、74%、65%（P〈0.05）。结论：姜黄素衍生物可以明显抑制原代肝星状细胞的增殖和活化,促进活化的肝星状细胞凋亡及减少细胞外基质的沉积。     

Betulin, betulinic acid and butein are inhibitors of acetaldehyde-induced activation of liver stellate cells

Liver fibrosis has been reported to be inhibited in vivo by oleanolic and ursolic acids; however, the activity of other triterpenes like betulin and betulinic acid has not been examined. Butein has also been reported to prevent and partly reverse liver fibrosis in vivo, although its mechanism of action is poorly understood. Therefore, the aim of this study was to determine the antifibrotic potential of butein, betulin, and betulinic acid and examine their mechanisms of action in vitro. This study was conducted in rat stellate cells (HSCs) that were treated with acetaldehyde, which is the most reactive product of ethanol metabolism. Butein, betulin, and betulinic acid were preincubated with rat HSCs at non-toxic concentrations. Treatment effects were measured in regard to acetaldehyde-induced toxicity and cell migration, and several markers of HSC activation were evaluated, including smooth muscle α-actin (α-SMA) and procollagen I expression. In addition, changes in the release of reactive oxygen species (ROS) and cytokines such as tumor necrosis factor-α (TNF-α) and tumor growth factor-β1 (TGF-β1) and changes in the production of metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were determined. In vitro, HSCs were protected against acetaldehyde-induced toxicity by betulin but not by betulinic acid and butein. However, butein, betulin, and betulinic acid inhibited the production of ROS by HSCs treated with acetaldehyde and inhibited their migration. Butein also inhibited acetaldehyde-induced TGF-β1 production. Butein, betulin, and betulinic acid down-regulated acetaldehyde-induced production of TIMP-1 and TIMP-2. Betulin decreased the acetaldehyde-induced activity of MMP-2, but butein and betulinic acid did not. The results indicated that butein, betulin, and betulinic acid inhibited the acetaldehyde-induced activation of HSCs. Each drug functioned in a different manner, whereby some were acting as either antioxidants or inhibitors of TIMPs expression and butein additionally acted as an inhibitor of TGF-β production.     

骨髓间充质干细胞调控肝星状细胞增殖和胶原合成的实验研究

目的研究骨髓间充质干细胞（BMSCs）对肝星状细胞（HSCs）增殖、胶原合成的影响。方法 （1）BMSCs对HSCs增殖的影响：利用transwell共培养体系,按1：1细胞比例在6孔塑料培养板上室接种BMSCs（1×105cells/well）,下室接种HSCs;对照组成纤维细胞代替BMSCs接种于上室;空白组为HSCs单独培养。培养24、48、72h后MTT法检测HSCs增殖抑制率;（2）BMSCs对HSCs胶原合成的影响：实验分为3组,A：HSCs组,B：HSCs＋TGF-β1组,C：共培养＋TGF-β1组。按上述方法进行BMSCs、HSCs共培养,培养液中加入TGF-β1诱导活化。培养72h后,取出BMSCs并换液,24h后收集培养液,用ELISA方法测定Ⅰ型胶原浓度,收集HSCs,RT-PCR检测HSCsα-SMA以及Ⅰ型胶原的基因表达。结果培养24、48、72 h后,共培养组较对照组可明显提高HSCs增殖抑制率（P〈0.01）;比较B组,C组Ⅰ型胶原浓度显著下降（P〈0.01）,同时HSCsα-SMA及Ⅰ型胶原基因表达出现显著下调（P〈0.01）。结论 BMSCs在体外可明显抑制HSCs增殖以及抑制TGF-β1诱导的α-SMA表达和Ⅰ型胶原合成。     

鬼针草总黄酮对肝纤维化大鼠肝星状细胞TGF-β1信号传导通路的影响

目的研究外源性转移生长因子-β1(transforming growth factor betal,TGF-β1)对肝星状细胞(hepatic stellate cells,HSC)的激活作用,观察鬼针草总黄酮(total flavonoids of Bidens Bipinnata L,TFB)对HSC中smad2/7和Ⅰ型胶原mRNA和蛋白表达的影响,以探讨TFB抗肝纤维化的作用及分子机制。方法采用Collagenase Ⅳ胶原酶原位肝灌注法分离HSC,MTT法观察TFB对TGF-β1刺激下HSC增殖的作用,ELISA法检测HSC自分泌TGF-β1和产生Ⅰ型胶原的影响;RT-PCR法观察分析TFB对TGF-β1刺激下HSC中smad2/7和Ⅰ型胶原基因表达的影响;Westernblot法观察TFB对TGF-β1刺激下HSC中smad2蛋白表达的影响。结果TGF-β1明显促进HSC增殖、自分泌TGF-β1和产生胶原,促进HSCsmad2、Ⅰ型胶原mRNA及smad2蛋白的表达,明显抑制smad7mRNA表达(P<0.05),TFB作用后,TGF-β1刺激的HSC中smads2mRNA、蛋白和Ⅰ型胶原mRNA表达受到抑制,smad7mRNA表达明显上调。结论TFB抗肝纤维化作用可能与其阻断HSCTGF-β1通路进而阻断HSC的活化、增殖有关。