吡非尼酮和尼达尼布抑制博来霉素诱导的小鼠肺纤维化药效比较

目的:比较不同时期给予吡非尼酮和尼达尼布对博来霉素诱导的小鼠肺纤维化的作用。方法:根据给药时间和给药时长,建立5类小鼠模型:炎症时期给药模型、纤维化早期预防给药模型、纤维化早期治疗模型、纤维化晚期治疗模型和全程给药模型,分别检测炎症指标和纤维化指标。结果:(1)抗炎抗氧化评估:吡非尼酮和尼达尼布均能降低炎症细胞数目,抑制炎症因子分泌。吡非尼酮对白细胞介素1β(IL-1β)和IL-4的抑制效果较好(P<0.01),尼达尼布对IL-6、IFN-γ的抑制作用较好(P<0.05)。吡非尼酮可显著提高超氧化物歧化酶(SOD)活性(P<0.01),而尼达尼布可显著降低丙二醛(MDA)和髓过氧化物酶(MPO)含量(P<0.01)。(2)肺组织胶原含量检测:在纤维化早期治疗模型、纤维化晚期治疗模型、全程给药模型中,尼达尼布对羟脯氨酸的抑制作用均优于吡非尼酮(P<0.05)。而吡非尼酮在纤维化早期预防给药模型中对羟脯氨酸的抑制作用较好(P<0.01)。(3)肺组织病理学评价:吡非尼酮和尼达尼布均可减少肺组织炎症浸润和纤维化面积,抑制效果对比结果同胶原检测结果一致。结论...     

吡非尼酮对大鼠坐骨神经损伤后瘢痕形成及功能恢复的实验研究

目的探讨大鼠坐骨神经损伤后细胞因子抑制剂吡非尼酮对神经吻合口处瘢痕形成及神经功能恢复的影响。方法选用健康雄性SD大鼠60只,制作右侧坐骨神经损伤模型,术后随机分为3组,分别为对照组、低剂量组和高剂量组,每组20只,分别给予0 mg/kg、25 mg/kg、100 mg/kg吡非尼酮混悬液灌胃。术后于第4、12周分别行坐骨神经功能指数、神经电生理测定,然后取材进行Ⅰ型胶原蛋白免疫组织化学染色,最终对实验结果进行图像分析和统计学处理。结果坐骨神经功能指数:术后第4周,三组之间两两比较,差异无统计学意义(P0.05);术后第12周,低剂量组优于对照组(P0.01),高剂量组优于低剂量组(P0.01);神经电生理:术后第4周,三组之间神经传导速度、潜伏期、波幅两两比较,差异无统计学意义(P0.05);术后第12周,与对照组相比,低剂量组和高剂量组神经传导速度显著增快(P0.05),潜伏期缩短(P0.05),波幅升高(P0.05),且高剂量组优于低剂量组(P0.05);Ⅰ型胶原蛋白沉积量:术后第4周,与对照组相比,低剂量组和高剂量组神经吻合口处Ⅰ型胶原蛋白沉积量明显减少(P0.01),低剂量组与高剂量组相比,差异无统计学意义(P0.05);术后第12周,与对照组相比,低剂量组和高剂量组神经吻合口处Ⅰ型胶原蛋白沉积量明显减少(P0.01),且高剂量组比低剂量组减少更明显(P0.05)。结论吡非尼酮能明显减少神经吻合口处Ⅰ型胶原蛋白沉积,有效抑制瘢痕形成,促进神经功能恢复。     

吡非尼酮抑制TGF-β1诱导的人肺成纤维细胞表型转化

目的:研究吡非尼酮(PFD)是否抑制转化生长因子β1(TGF-β1)诱导的人肺成纤维细胞(HLFs)表型转化。方法:MTT法检测细胞存活率;Ed U法检测细胞的增殖能力;Transwell实验检测细胞的迁移和侵袭能力,Western blot法和细胞免疫荧光检测α-平滑肌肌动蛋白(α-SMA)的蛋白水平,实时荧光定量PCR检测α-SMA和Ⅰ、Ⅲ型胶原蛋白的mRNA表达水平。结果:不同浓度的吡非尼酮(0.1、0.2、0.3、0.5和0.8 mg/L)无明显的细胞毒性作用,后续实验应用0.2 mg/L为干预浓度。吡非尼酮(0.2 mg/L)预处理HLFs能明显地抑制TGF-β1诱导的细胞增殖、迁移和侵袭能力,下调Ⅰ、Ⅲ型胶原蛋白的mRNA表达水平(P0.05),并且干扰TGF-β1诱导的细胞骨架重组和表型转化,使α-SMA的mRNA和蛋白水平均下降(P0.05)。结论:吡非尼酮能有效地抑制TGF-β1所诱导的HLFs细胞功能和表型转化。     

安络化纤丸抗肝纤维化机制探讨

为探讨安络化纤丸抗肝纤维化的作用机制，笔者采用安络化纤丸治疗慢性乙型肝炎肝纤维化，观察了治疗前后血清肝纤维化指标和基质金属蛋白酶-2（MMP-2）的变化情况，报告如下。     

柔肝方通过抑制纤维化蛋白抗肝纤维化的机制研究

目的:柔肝方是上海市名中医王灵台教授治疗肝纤维化的临床有效验方,本研究旨在探讨柔肝方通过抑制纤维化蛋白(FBRS)抗肝纤维化的分子机制.方法:质谱法鉴定柔肝方的化学成分及其入血成分.BALB/c小鼠随机分对照组、模型组、柔肝方高剂量组、柔肝方中剂量组和柔肝方低剂量组.通过尾静脉注射ConA(12.5 mg/kg),每周...     

肝纤维化发病机制的研究进展

肝纤维化是对慢性肝损伤的一种修复反应,肝纤维化的特征改变是肝脏内细胞外基质（extracellular matrix,ECM）的过度沉积。肝星状细胞（hepatic stellate cells, HSCs）的活化被认为是这一过程中的关键事件。在纤维形成过程中,促纤维形成细胞、细胞因子、生长因子、酶及其抑制因子发挥了十分重要的作用。     

红景天抗肝纤维化研究进展

本文阐述了红景天的分布及主要有效成分、肝纤维化机制以及红景天抗纤维化相关机制。     

红景天抗肝纤维化研究进展

本文阐述了红景天的分布及主要有效成分、肝纤维化机制以及红景天抗纤维化相关机制。     

非侵入性检查方法评价肝纤维化的研究进展

肝纤维化程度是评估慢性肝病演变过程及预后的重要指标,判断肝纤维化程度对慢性肝病的诊疗管理十分重要。肝活检被认为是评估炎症坏死和纤维化程度的“金标准”。一些非侵入性评估方法检测结果因与肝活检符合度较高已被纳入慢性肝病诊疗管理的相关指南中,但这些无创性检测方法易受多种因素干扰,其准确性、重复性和可比性尚有待进一步提高。本文对近年有关肝纤维化非侵入性诊断方法的进展做一综述。     

Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) consists of oculocutaneous albinism, a platelet storage pool deficiency and, in patients with HPS1 gene mutations, a progressive, fatal pulmonary fibrosis. We investigated the safety and efficacy of an antifibrotic agent, pirfenidone (800 mg, t.i.d.), in treating 21 adult Puerto Rican HPS patients, including 20 homozygous for the same HPS1 mutation. Patients were examined every 4 months for up to 44 months in a randomized, placebo-controlled trial, with rate of change in pulmonary function values as outcome parameters. Using the complete data set of 130 patient admissions, a repeated measures model showed that 11 pirfenidone-treated patients lost FVC at a rate 5% of predicted ( approximately 400 mL) per year slower than 10 placebo-treated patients (p=0.001). A random coefficients model showed no significant difference. However, using data restricted to patients with an initial FVC >50% of predicted, both models showed the pirfenidone group losing FVC (p<0.022), FEV(1) (p<0.0007), TLC (p<0.001), and DL(CO) (p<0.122) at a rate approximately 8%/year slower than the placebo group. Clinical and laboratory side effects were similar in the two groups. Pirfenidone appears to slow the progression of pulmonary fibrosis in HPS patients who have significant residual lung function.     

Hepatoprotection by malotilate against carbon tetrachloride-alcohol-induced liver fibrosis

Subchronic treatment of male rats with carbon tetrachloride (CCl₄, twice weekly 0.2 ml/kg p.o) and feeding a 5% alcohol solution instead of drinking water led to a nearly complete liver cirrhosis in all animals within 4 weeks. This was also documented by a three fold increase in hepatic total hydroxyproline content. Steatosis was quantified by enhanced liver triglyceride concentrations and acute necroses by increments of serum enzyme activities (GPT, SDH). Daily oral treatment with malotilate (100 mg/kg) totally prevented the development of liver cirrhosis, hepatic hydroxyproline accumulation and increases in serum enzyme activities induced by CCl₄-alcohol. In cianidanol-treated rats (100 mg/kg p.o.) only portoseptal fibrosis was seen, however hydroxyproline and triglyceride accumulation as well as enhanced serum enzyme activities were not suppressed. D-penicillamine (300 mg/kg p.o.) and colchicine (50 g/kg i.p.) failed to protect rats against CCl₄-alcohol induced fibrosis, necrosis and steatosis in this model.     

Hyperoside protects against heart failure-induced liver fibrosis in rats

Heart failure (HF) is an end-stage of various serious cardiovascular diseases, which causes liver injury. Hyperoside has been reported to exert protective effect on liver injury and fibrosis. However, the role and related mechanisms of hyperoside in HF-induced liver fibrosis are still unclear. In the current study, we established a model of HF via aortocaval fistula (ACF) in rats in vivo. Hyperoside treatment in ACF rats increased cardiac output, the maximum peak rate of rise/fall in left ventricular pressure (+dP/dt, -dP/dt) and LV ejection fraction (LVEF), decreased LV end-systolic pressure (LVESP), LV end-diastolic pressure (LVEDP) and LV end-systolic volume (LVESV), and reduced heart weight/body weight ratio in a dose-dependent manner. Moreover, hyperoside could attenuate liver fibrosis and injury in ACF rats, as evidenced by reduction of fibrosis area and hydroxyproline content, amelioration of edema and degeneration of liver cell vacuoles, and inhibition of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels. Further, α-smooth-muscle actin (α-SMA), collagen I, profibrotic factor-connective tissue growth factor (CTGF), matrix metalloproteinase-2 (MMP2) and MMP9 levels were down-regulated in hyperoside-treated ACF rats. Additionally, hyperoside inhibited the activation of TGF-β1/Smad pathway. Finally, we confirmed that hyperoside suppressed TGF-β1-mediated hepatic stellate cell activation in vitro. Collectively, hyperoside showed a suppressive role in HF-induced liver fibrosis and injury.     

Effects of dithiocarb and (+)-catechin against carbon tetrachloride-alcohol-induced liver fibrosis

Treatment of male rats with carbon tetrachloride (CCl₄, 2 × weekly 0.2 ml/kg p.o.) and a 5% alcohol solution, instead of drinking water, for 4 weeks led to marked increases in serum enzyme activities (GOT, GPT, SDH), hepatic triglyceride and hydroxyproline content. Diethyl dithiocarbamate (dithiocarb, 200 mg/kg p.o.) simultaneously applied with CCl₄ totally suppressed the elevation in serum enzyme activities and hepatic hydroxyproline concentration, and partially suppressed that of the triglyceride content. (+)-Catechin (50–300 mg/kg p.o.). simultaneously applied with CCl₄ had no influence on the enhanced serum enzymes, but depressed the augmented content of both hepatic triglyceride and hydroxyproline in a dose-dependent way. The most effective dose with respect to the reduction of the hydroxyproline concentration was 100 mg/kg (+)-catechin; the highest dose (300 mg/kg), however, enhanced the CCl₄-alcohol-induced hydroxyproline augmentation.     

Artemisia capillaris extract protects against bile duct ligation-induced liver fibrosis in rats

Artemisia capillaris has been widely used as a traditional herbal medicine in the treatment of liver diseases. However, no previous study has investigated whether A. capillaries alone is effective in treating pathological conditions associated with cholestatic liver injury. In the present study, we evaluated the anti-hepatofibrotic effects of A. capillaris (aqueous extract, WAC) in a bile duct ligation (BDL)-induced cholestatic fibrosis model. After BDL, rats were given WAC (25 or 50 mg/kg) or urosodeoxycholic acid (UDCA, 25 mg/kg) orally for 2 weeks (once per day). The serum cholestatic markers, malondialdehyde, and liver hydroxyproline levels were drastically increased in the BDL group, while administering WAC significantly reduced these alterations. Administering WAC also restored the BDL-induced depletion of glutathione content and glutathione peroxidase activity. Cholestatic liver injury and collagen deposition were markedly attenuated by WAC treatment, and these changes were paralleled by the significantly suppressed expression of fibrogenic factors, including hepatic alpha-smooth muscle actin (α-SMA), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-β). The beneficial effects of WAC administration are associated with antifibrotic properties via both upregulation of antioxidant activities and downregulation of ECM protein production in the rat BDL model.     

Effect of Fuzheng Huayu formula and its actions against liver fibrosis

Liver fibrosis is a common histological process to develop into cirrhosis in various chronic liver diseases including chronic hepatitis and fatty liver. Therefore anti-liver fibrosis is very important strategy to treat chronic liver diseases. Fuzheng Huayu (FZHY), a preparation containing herbs such as Radix Salvia Miltiorrhizae, Cordyceps, Semen Persicae, was formulated on the basis of Chinese medicine theory in treating liver fibrosis and was approved. Pharmacological studies and clinical trials demonstrate that FZHY has a significant effect against liver fibrosis and that many of the pharmacological actions are attributable to the effect. This article reviews the effects and actions of FZHY, in particular the effects observed from clinical trials in treating liver fibrosis caused by chronic hepatitis B and the actions on inhibition of hepatic stellate cell activation, protection of hepatocytes and inhibition of hepatic sinusoidal capillarization. This article also reviews the coordinated effects of the constituent herbs of FZHY and the actions of their active compounds such as salvianonic acid B (SA-B) on liver fibrosis.     

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。     

Endocytic collagen degradation: a novel mechanism involved in protection against liver fibrosis

Fibrosis of the liver and its end-stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions, activated fibroblasts and hepatic stellate cells display a net deposition of collagen. This collagen deposition is a major factor leading to liver dysfunction, thus making it crucially important to understand both the collagen synthesis and turnover mechanisms in this condition. Here we show that the endocytic collagen receptor, uPARAP/Endo180, is a major determinant in governing the balance between collagen deposition and degradation. Cirrhotic human livers displayed a marked up-regulation of uPARAP/Endo180 in activated fibroblasts and hepatic stellate cells located close to the collagen deposits. In a hepatic stellate cell line, uPARAP/Endo180 was shown to be active in, and required for, the uptake and intracellular degradation of collagen. To evaluate the functional importance of this collagen receptor in vivo, liver fibrosis was induced in uPARAP/Endo180-deficient mice and littermate wild-type mice by chronic CCl(4) administration. A strong up-regulation of uPARAP/Endo180 was observed in wild-type mice, and a quantitative comparison of collagen deposits in the two groups of mice clearly revealed a fibrosis protective role of uPARAP/Endo180. This effect appeared to directly reflect the activity of the collagen receptor, since no compensatory events were noted when comparing the mRNA expression profiles of the two groups of mice in an array system focused on matrix-degrading components. This function of uPARAP/Endo180 defines a novel role of intracellular collagen turnover in fibrosis protection.