Histone deacetylase inhibitor suberoylanilide hydroxamic acid alleviates liver fibrosis by suppressing the transforming growth factor-β1 signal pathway

Background: Histone deacetylases(HDACs) inhibitors are new anti-fibrotic drugs that inhibit the activity of hepatic stellate cells. The present study focused on the anti-fibrotic function of HDAC inhibitor suberoylanilide hydroxamic acid(SAHA) by suppressing transforming growth factor-β1(TGF-β1) signaling. Methods: Male Sprague-Dawley rats were used to induce liver fibrosis with carbon tetrachloride(CCl 4) and LX2 cell(human hepatic stellate cell line) was stimulated by TGF-β1. Both animals and cells were treated with SAHA. The Smad7 and connective tissue growth factor(CTGF) mRNA levels were detected by real-time polymerase chain reaction(PCR). Western blotting was used to examine the protein levels of CTGF, Histone H3(H3), Smad7, Smad2/3, Acetyl-Histone H3(AH3), HDAC2, α-smooth muscle actin( α-SMA), HDAC6, p-Smad2/3 and HDAC8. In addition, the TGF-β1 and liver enzyme levels from rat serum were detected. Histopathological changes were examined by hematoxylin and eosin(HE), Sirius red and Masson trichrome staining. The α-SMA expression was detected by immumohistochemical staining. Results: Compared with control group, the TGF-β1 and liver enzyme levels from rat serum, together with the mRNA levels of CTGF and protein levels of CTGF, HDAC2, α-SMA, HDAC6, p-Smad2/3 and HDAC8 were elevated in fibrotic rats( P < 0.01). But the Smad7 mRNA and AH3 protein levels were notably suppressed in the fibrotic rats( P < 0.01). Pathological examination showed the typical changes of liver fibrosis in the fibrotic rats. After the treatment with SAHA, the levels of liver enzymes, TGF-β1, CTGF, HDAC2, α-SMA, HDAC6, p-Smad2/3 and HDAC8 were reduced( P < 0.01) and Smad7 and AH3 protein contents were elevated in liver fibrotic rats( P < 0.01). Moreover, immumohistochemistry showed that SAHA significantly suppressed the α-SMA protein content in fibrotic liver( P < 0.01). Conclusion: The HDAC inhibitor SAHA alleviated liver fibrosis by suppressing the TGF-β1 signaling.

Vascular endothelial growth factor A, secreted in response to transforming growth factor-β1 under hypoxic conditions, induces autocrine effects on migration of prostate cancer cells

Hypoxia and transforming growth factor-β1 （TGF-β1） increase vascular endothelial growth factor A （VEGFA） expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-β1 was shown to induce VEGFA165 secretion from both normal cell lines （HPV7 and RWPE1） and prostate cancer cell lines （DU 145 and PC3）. Conversely, hypoxia-stimulated VEGFA165 secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-β1 expression in PC3 prostate cancer cells, and the TGF-β1 type I receptor （ALK5） kinase inhibitor partially blocked hypoxia-mediated VEGFA16s secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor （VEGFR） 1 （Fit-l） and 2 （FIk-I/KDR）. Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA165 treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 （ERKI/2） in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA165 was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-β1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-β1 and hypoxia on metastatic prostate cancers.

The Effect of Simvastatin on mRNA Expression of Transforming Growth Factor-β1,Bone Morphogenetic Protein-2 and Vascular Endothelial Growth Factor in Tooth Extraction Socket

Aim To determine the effect of local simvastatin application on the mRNA expression level of transforming growth factor-β1 （TGF-β1）, bone morphogenetic protein-2 （BMP-2） and vascular endothelial growth factor （VEGF） in the tooth sockets of rat. Methodology Forty-eight male Wistar rats were randomly divided into experimental and control groups （n=24）. Polylactic acid/polyglycolic acid copolymer carriers, with or without simvastatin, were implanted into extraction sockets of right mandibular incisors. The expression of TGF-β1, BMP-2 and VEGF mRNA was determined by in situ hybridization in the tooth extraction socket at five days, one week, two weeks and four weeks after implantation. Results The fusiform stroma cells in the tooth extraction socket began to express TGF-β1, BMP-2 and VEGF mRNA in both experimental and control groups from one week after tooth extraction until the end of experiment. The expression of TGF-131 and BMP-2 mRNA in the experimental group was significantly up-regulated after one, two and four weeks, and expression of VEGF mRNA was significantly increased after one and two weeks compared with that in the control group. Conclusion The findings indicate that local administration of simvastatin can influence alveolar bone remodeling by regulating the expression of a school of growth factors which are crucial to osteogenesis in the tooth extraction socket.

慢性肝病患者PBMC中TGF-β_1mRNA表达及其与肝纤维化的关系

目的 :研究转化生长因子 β1(transforminggrowthfactor β1,TGF β1)在慢性肝病患者外周血单个核细胞 (peripheralbloodmononuclearcell,PBMC)中的表达及其与肝纤维化的关系。方法 :用定量RT PCR法 (RT PCR加Dotblot法 )检测轻、中、重度慢性肝炎、肝炎后肝硬变活动期患者和与之对照的正常人PBMC中TGF β1mR NA水平 ,并对其与肝纤维化血清学指标的关系进行统计学分析。结果 :慢性轻、中、重度肝炎和肝炎后肝硬变活动期PBMC中TGF β1mRNA分别为 1.47± 0 .47、1.90± 0 .5 3、3.0 9± 1.44和 3.2 1± 0 .91,显著高于对照组(0 .78± 0 .41) (P <0 .0 1)。肝纤维化血清学指标增高≥三项患者组和增高 <三项患者组PBMC中TGF β1mR NA分别为 2 .6 2± 1.14和 1.6 1± 0 .5 1,亦显著高于对照组 (P <0 .0 1,P <0 .0 5 ) ,其中增高≥三项患者组的TGF β1mRNA水平尚高于增高 <三项患者组 (P <0 .0 1)。结论 :TGF β1在慢性病毒性肝炎患者PBMC中表达增高 。

肝硬化患者肝组织中IGFBPrP1与TGF-β_1/Smad3信号通路的相关性研究

目的探讨肝硬化患者肝组织中胰岛素样生长因子结合蛋白相关蛋白1(IGFBPrP1)与转化生长因子(TGF)-β1/Smad3信号通路的可能关系。方法31例肝组织蜡块来自2002年1月至2007年12月山西医科大学第一医院病理科。其中肝硬化组16例,对照组15例为手术切除肝血管瘤外正常肝组织。蜡块5μm厚连续切片,行苏木素-伊红(HE)及Masson染色,免疫组织化学染色观察肝组织中IGFBPrP1、TGF-β1及Smad3的表达,收集肝硬化组16例患者的血清透明质酸(HA)实验室检查结果。结果HE及Masson染色结果显示对照组肝细胞形态正常、排列整齐,肝小叶结构完整;肝硬化组小叶结构被破坏,形成假小叶。肝硬化患者肝组织IGF-BPrP1、TGF-β1、Smad3的表达比正常对照组明显升高,且肝组织IGFBPrP1的表达分别与肝组织胶原纤维面积、TGF-β1、Smad3及血清HA呈正相关。结论IGFBPrP1在肝硬化的发生发展中起重要作用,且该作用可能与TGF-β1/Smad3信号转导通路有关。

慢性肝病患者血清TGF-α和TGF-β_1的检测及意义

目的 :探讨慢性肝病患者血清 TGF- α和 TGF- β1 的变化及其意义。方法 :用放免法和双抗体夹心 EL ISA法分别测定10 4例慢性肝病患者血清的 TGF- α和 TGF- β1 。结果 :慢性肝炎、肝硬化及原发性肝癌患者血清的 TGF- α和 TGF- β1 含量均显著升高 ;原发性肝癌患者的 TGF- α明显高于慢性肝炎及肝硬化患者 ;血清的 TGF- α和 TGF- β1 在各组患者中呈显著的正相关。结论 :检测血清 TGF- α和 TGF- β1 ,对于慢性肝炎。

肝硬变患者TGF-β_1基因在外周血中表达及与PⅢP血清水平的关系

目的:为验证肝纤维化动物模型和慢性肝病患者肝组织中,转化生长因子(TGF-β1)的mRNA表达增强。作者分析肝硬变患者外周血TGF-β1mRNA和血清中有活性的TGF-β1蛋白及其结果与型前胶原N端肽(PP)血清水平间的关系。方法:肝硬变患者50例,健康自愿者8人,取其外周血,分离单核细胞(PBMC),提取总RNA,用巢式RT-PCR扩增TGF-β1mRNA并测定血清中TGF-β1和PP的水平。结果:分析表明患者外周血单核细胞(PBMC)中TGF-β1mRNA有高阳性率的表达。血清中TGF-β1与PP的水平均明显高于对照。结论:研究结果证实肝硬变患者TGF-β1基因在外周血中表达增强,与PP血清水平相关,表明TGF-β1可能在肝纤维化。

Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model

AIM:To investigate whether transforming growth factor-β1(TGF-β1)signaling pathway is involved in the pathogenesis of primary biliary cirrhosis(PBC).METHODS:A murine model of PBC was developed by injection of polyinosinic polycytidylic acids(polyⅠ:C)in C57BL/6 mice,and the liver expressions of TGFβ1,TGF-βreceptorⅠ(TβRⅠ),TGF-βreceptorⅡ(TβRⅡ),p-Smad2/3,monoclonalα-smooth muscle actin antibody(α-SMA)andα1(Ⅰ)collagen in the mouse model and control mice were evaluated by immunohistochemistry,immunoblotting and real-time polymerase chain reaction(RT-PCR).Lymphocyte subsets in liver were analyzed using flow cytometry.RESULTS:The mouse model had several key phenotypic features of human PBC,including elevated levels of alkaline phosphatase,antimitochondrial antibodies,portal bile ducts inflammation,and progressive collagen deposition.Compared with control mice,protein and mRNA levels of TGFβ1,TβRⅠ,TβRⅡ,p-Smad2/3,α-SMA andα1(Ⅰ)collagen in liver(1.7±0.4 vs 8.9±1.8,0.8±0.2 vs 5.1±1.5,0.6±0.01 vs5.1±0.1,0.6±0.3 vs 2.0±0.3,0.9±0.4 vs 3.4±0.6,0.8±0.4 vs 1.7±0.3,1.1±1.2 vs 11.8±0.6,P<0.05),and the total number and percentage of CD4+CD25+FOXP3+and CD8+lymphocytes(0.01±0.001vs 0.004±0.00,0.12±0.04 vs 0.52±0.23,P<0.01)were higher in the mouse model.CONCLUSION:TGFβ1 might play a dual role in the development of PBC:it suppresses inflammatory response but operates to enhance fibrogenesis.The aberrant activity of TGF-β1 signaling contributes to the development of PBC.

Transforming growth factor beta-1 upregulates glucose transporter 1 and glycolysis through canonical and noncanonical pathways in hepatic stellate cells

BACKGROUND Hepatic stellate cells(HSCs)are the key effector cells mediating the occurrence and development of liver fibrosis,while aerobic glycolysis is an important metabolic characteristic of HSC activation.Transforming growth factor-β1(TGF-β1)induces aerobic glycolysis and is a driving factor for metabolic reprogramming.The occurrence of glycolysis depends on a high glucose uptake level.Glucose transporter 1(GLUT1)is the most widely distributed glucose transporter in the body and mainly participates in the regulation of carbohydrate metabolism,thus affecting cell proliferation and growth.However,little is known about the relationship between TGF-β1 and GLUT1 in the process of liver fibrosis and the molecular mechanism underlying the promotion of aerobic glycolysis in HSCs.AIM To investigate the mechanisms of action of GLUT1,TGF-β1 and aerobic glycolysis in the process of HSC activation during liver fibrosis.METHODS Immunohistochemical staining and immunofluorescence assays were used to examine GLUT1 expression in fibrotic liver tissue.A Seahorse extracellular flux(XF)analyzer was used to examine changes in aerobic glycolytic flux,lactate production levels and glucose consumption levels in HSCs upon TGF-β1 stimulation.The mechanism by which TGF-β1 induces GLUT1 protein expression in HSCs was further explored by inhibiting/promoting the TGF-β1/mothersagainst-decapentaplegic-homolog 2/3(Smad2/3)signaling pathway and inhibiting the p38 and phosphoinositide 3-kinase(PI3K)/AKT signaling pathways.In addition,GLUT1 expression was silenced to observe changes in the growth and proliferation of HSCs.Finally,a GLUT1 inhibitor was used to verify the in vivo effects of GLUT1 on a mouse model of liver fibrosis.RESULTS GLUT1 protein expression was increased in both mouse and human fibrotic liver tissues.In addition,immunofluorescence staining revealed colocalization of GLUT1 and alpha-smooth muscle actin proteins,indicating that GLUT1 expression was related to the development of liver fibrosis.TGF-β1 caused an increase in aerobic glycolysis in HSCs and induced GLUT1 expression in HSCs by activating the Smad,p38 MAPK and P13K/AKT signaling pathways.The p38 MAPK and Smad pathways synergistically affected the induction of GLUT1 expression.GLUT1 inhibition eliminated the effect of TGF-β1 on HSC proliferation and migration.A GLUT1 inhibitor was administered in a mouse model of liver fibrosis,and GLUT1 inhibition reduced the degree of liver inflammation and liver fibrosis.CONCLUSION TGF-β1 induces GLUT1 expression in HSCs,a process related to liver fibrosis progression.In vitro experiments revealed that TGF-β1-induced GLUT1 expression might be one of the mechanisms mediating the metabolic reprogramming of HSCs.In addition,in vivo experiments also indicated that the GLUT1 protein promotes the occurrence and development of liver fibrosis.

转化生长因子-β_1对鼠肝细胞凋亡调控作用的研究

目的 :本研究旨在明确正常肝和肝硬化肝细胞中转化生长因子 β1(TGF β1)的作用及其与凋亡的关系。 方法 :通过 5 0 %四氯化碳 (CCl4)腹腔注射诱发BALB/c小鼠形成肝硬化模型 ;应用改良的胶原酶原位灌注法分离正常和肝硬化小鼠的肝细胞 ;利用 1.5 %的琼脂糖凝胶电泳观察DNA梯形条带 ,并应用DNA荧光染料Hoechst33342对正常肝细胞进行染色 ,以检测TGF β1诱导的凋亡。 结果 :以胶原酶原位二步灌流法分离肝细胞的活率为 95 .2 %。正常肝细胞予以TGF β1处理后 ,应用 1.5 %的琼脂糖凝胶电泳可以发现具有凋亡特征的梯形条带。硬化肝细胞则很少出现梯形条带。经TGF β1处理的正常肝细胞应用Hoechst染色发现 ,其凋亡率明显高于未处理组。 结论 :肝硬化肝细胞不能像正常肝细胞那样发生TGF β1诱导的凋亡 。

肝硬化患者血清转化生长因子β_1水平与Child-pugh分级的关系

为探讨肝硬化患者血清转化生长因子(TGF-β1)水平变化及与Child-Pugh分级的关系。用ELISA法测定了93例肝硬化患者及50例健康人血清TGF-β1水平。结果显示,肝硬化患者血清TGF-β1较对照组显著升高(P<0．01)且由Child A级到Child C级逐渐升高,各组间均有显著性差异(P<0．01)。提示血清TGF-β1是反映肝硬化患者肝功能损害程度的指标之一,可用于判断肝硬化患者肝功能损害程度及评价预后。

转化生长因子β_1在白细胞介素10干预肝纤维化大鼠肝星形细胞的表达

目的 探讨转化生长因子 β1(TGF β1)在白细胞介素 10 (IL 10 )干预肝纤维化大鼠星形细胞中的表达 ,阐明外源性IL 10的抗纤维化作用及可能机制。 方法 6 0只雄性SD大鼠随机分为正常对照组 (N组 ,8只 )、肝纤维化模型组 (C组 ,2 8只 )和IL 10干预组 (I组 ,2 4只 ) ,分别于CCl4造模第 7周及 11周采用链霉蛋白酶E、Ⅳ型胶原酶经门静脉灌注分离肝星形细胞。半定量RT PCR法检测各组新分离肝星形细胞中TGF β1mRNA的表达水平 ;SP免疫细胞化学法检测各组原代培养 72h后肝星形细胞TGF β1蛋白的表达水平。并于上述两个时间段分别将各组肝组织行苏木精 伊红染色判断炎症和肝纤维化程度。 结果 成功建立大鼠肝纤维化模型及IL 10干预模型 ,并对大鼠肝星形细胞进行分离及原代培养。与正常组相比 ,纤维化模型组TGF β1的mRNA水平显著升高(P <0 0 1) ,经IL 10干预后则明显降低 (P <0 0 1)。纤维化模型组星形细胞TGF β1mRNA水平在第 11周时低于第 7周 (P <0 0 5 )。SP免疫细胞化学法检测各组TGF β1的蛋白表达情况与mRNA结果相平行。 结论 IL 10可抑制肝纤维化大鼠星形细胞中TGF β1表达 ,具有抗纤维化作用。

肝硬化组织转化生长因子β_1的分布研究及临床意义

目的研究转化生长因子β1(TGFβ1)、胶原纤维和网状纤维在肝硬化组织中的分布、意义及肝细胞癌变对其分布的影响。方法采用免疫组织化学SP法检测30例肝硬化组织和1例大致正常肝组织TGFβ1的表达情况。用Masson染色显示胶原纤维,GordonSweet染色显示网状纤维。CMIAS-8彩色图像分析系统对阳性目标进行分析处理。结果(1)TGFβ1主要位于肝非实质细胞胞浆内,这些细胞主要分布在汇管区、纤维间隔、炎症区;纤维组织中有少量TGFβ1存在;少数肝细胞胞浆内也表达TGFβ1,总阳性率为20%,肝炎肝硬化组TGFβ1阳性表达率与肝炎肝硬化合并原发性肝细胞癌组比较无显著性差异(P>0.05);(2)肝炎肝硬化组TGFβ1的IOD为395.3±291.3,胶原纤维的AD为(6.3±3.8)%,网状纤维的AD为(5.4±2.3)%。TGFβ1的IOD与胶原纤维的AD呈正相关(r=0.8991,P<0.01),与网状纤维的AD呈正相关(r=0.8317,P<0.01);肝炎肝硬化合并原发性肝细胞癌组TGFβ1的IOD为840.7±449.6,胶原纤维的AD为(12.5±4.9)%,网状纤维的AD为(9.2±3.2)%。TGFβ1的IOD与胶原纤维的AD呈正相关(r=0.8025,P<0.01),与网状纤维的AD无相关(r=0.4314,P>0.05)。肝炎肝硬化组TGFβ1的表达、胶原纤维和网状纤维分布与肝炎肝硬化合并原发性肝细胞癌组比较均有显著性差异(P均<0.01);(3)胶原纤维主要分布在汇管区、纤维隔,炎症区,肝窦旁也可见少量存在;网状纤维主要分布在汇管区、纤维隔、炎症区、肝窦旁、实质细胞周围;原发性肝癌及外周肝硬化组织Gordon-Sweet染色显示:肝癌细胞区网状纤维不显色。结论TGFβ1与肝纤维化肝硬化的发生发展密切相关。在肝炎肝硬化,TGFβ1表达增强,当合并原发性肝细胞癌时,TGFβ1有极强表达;TGFβ1可作为原发性肝细胞癌的血清学辅助诊断,Gordon-Sweet染色可作为原发性肝细胞癌的病理学辅助诊断。

Genetic expression of Col-2A and Col-10A as a function of administration of IGF-1 &TGF-<i>β</i>with and without anterior mandibular repositioning appliance on the growth of mandibular condylar cartilage in young rabbit

New Zealand (NZ) young rabbits with the administration of insulin-like growth factor (IGF-1) and transforming growth factor-β (TGF-β) with and without mandibular anterior repositioning appliances are explored for the growth of the mandibular condylar cartilage (MCC). 32 growing NZ and rabbits were divided into 4 groups: the group with saline injection in TMJ, the group which received growth factor injection in TMJ, the group which received anterior positioning appliance and the group which received growth factors injection as well as mandibular repositioning appliance. Gene expression was studied by real-time RT-PCR and cartilage growth by histomorphometry. Administration of growth factors along with mandibular repositioning appliances has induced 1) 1.70-fold expression of Col-2Agene (p value < 0.0005) and 2) 1.47-fold expression of Col-10Agene (p value < 0.0005). In contrast, administration of only mandibular repositioning appliances induced 1) 1.28-fold expression of Col-2Agene (p value < 0.0005) and 2) merely 0.62-fold expression of Col-10Agene (p value < 0.0005), while administration of growth factors only induced 1) mere 0.56-fold expression of Col-2Agene (p value 10A gene (p value growth factors along with mandibular repositioning appliances causes an increase in genetic expressions which have been corroborated by histomorphometry and validated by statistical analysis, during an accelerated growth of mandibular condylar cartilage. Administration of growth factors in the TMJ could provide a synergistic role along with mandibular repositioning appliances for treatment of mandibular retrognathism as well as disorders on the MCC.

Regulation Mechanism of TFP on TGF-β1/STAT3 Signaling Pathway in Immune-mediated Liver Injury in Mice

[Objectives]To study the effect of total flavonoids extracted from Polygonum perfoliatum L.(TFP)on immune-mediated liver injury induced by bacillus Calmette-Guerin plus lipopolysaccharide(BCG+LPS)in mice,and to explore its action mechanism.[Methods]60 Kunming mice were divided into normal group,model group,control group(bifendate)and TFP low,medium and high dose groups according to random number table method,with 10 mice in each group.On the first day of modeling,mice were injected with 0.2 mL of BCG solution(12.5 mg/mL)through the tail vein,and on the eleventh day,0.2 mL of LPS(37.5μg/mL)were injected into the tail vein to prepare a mouse model of immune-mediated liver injury;from the first day of modeling,the normal group and the model group were administered intragastrically with the corresponding volume of distilled water,and the bifendate group and the TFP high,medium,and low dose groups were administered intragastrically with the corresponding doses once a day for 11 d.After the last time administration,fasting but giving water for 16 h,took blood from eyes,then collected the liver tissue.The levels of alanine transaminase(ALT)and aspartate transaminase(AST)in serum were detected by biochemical method;transforming growth factor-β1(TGF-β1),intercellular adhesion molecule-1(ICAM-1),interleukin-6(IL-6)and interleukin-1β(IL-1β)expression levels in liver tissue were detected by enzyme-linked immunosorbent assay(ELISA);phosphorylated protein tyrosine kinase JAK-2(p-JAK2),phosphorylated signal transducer and activator of transcription 3(p-STAT3)protein expression levels were detected by Western Blot method;the degree of liver tissue lesions was detected by HE staining.[Results]Compared with the model group,the levels of ALT and AST in the serum of mice in each dose group of TFP(high dose 600 mg/kg,medium dose 400 mg/kg,and low dose 200 mg/kg)were reduced,and the activities of T-SOD and GSH-Px were increased;the content or expression ofβ1,ICAM-1,IL-6,IL-1βdecreased,and the expression of p-JAK2 and p-STAT3 protein decreased;pathological sections showed that the degree of inflammatory necrosis and the degree of lesions in the liver tissues of each dose group of TFP were reduced by varying degrees.[Conclusions]TFP has a protective effect on BCG+LPS-induced immune-mediated liver injury in mice.The mechanism may be related to regulating the phosphorylation level of JAK2 and inhibiting the inflammatory reaction,thereby regulating the TGF-β1/STAT3 signaling pathway and improving the immune-mediated liver injury.

慢性乙型肝炎和肝硬化患者血清TLR4、TGF-β1和IL-17水平及其临床意义

目的分析慢性乙型肝炎(CHB)和乙型肝炎肝硬化患者血清Toll样受体4(TLR4)、转化生长因子-β1(TGF-β1)和白细胞介素-17(IL-17)水平变化及其临床意义。方法 2015年6月~2017年4月本院收治的112例CHB、52例乙型肝炎肝硬化患者和选择的33例健康人,采用ELISA法检验血清IL-17、TLR4、TGF-β1水平,常规进行肝活检。结果慢性乙型肝炎、肝硬化和健康人血清IL-17水平分别为(264.42±32.53)pg/ml、(271.54±33.71)pg/ml和(64.18±5.52)ng/ml,血清TLR4水平分别为(5.81±0.83)pg/ml、(37.41±6.05)pg/ml和(1.07±0.13)ng/ml,血清TGF-β1水平分别为(3.67±0.42)pg/ml、(7.82±1.07)pg/ml和(1.61±0.07)ng/ml,差异明显(P<0.05);19例Child-Pugh B级血清IL-17、TLR4和TGF-β1水平分别为(231.38±28.67)pg/ml、(18.61±2.87)pg/ml和(5.76±0.52)ng/ml,16例C级患者分别为(301.72±32.72)pg/ml、(39.47±6.82)pg/ml和(9.42±1.27)ng/ml,均明显高于17例Child-Pugh A级患者【分别为(204.53±26.57)pg/ml、(4.72±0.71)pg/ml和(3.18±0.34)ng/ml,P<0.05】;肝活检组织学检查发现S0 8例、S1 42例、S2 43例、S3 19例、S4 52例,血清IL-17、TLR4、TGF-β1水平随着肝组织纤维化分期严重而升高。结论乙型肝炎肝硬化患者血清TLR4、TGF-β1和IL-17水平升高,对诊断和指导治疗可能有帮助。

PDGF-BB、TGF-β1与肝纤维化的相关性研究

目的研究血小板衍生生长因子-BB(PDGF-BB)、转化生长因子-β1(TGF-β1)与肝纤维化的关系及对肝纤维化的诊断价值。方法以56例正常体检人员为对照组,123例慢性乙肝患者为观察组,比较两组PDGF-BB、TGF-β1血清标志物水平并比较观察组中不同肝纤维化程度PDGF-BB、TGF-β1血清标志物水平。结果观察组PDGF-BB、TGF-β1血清水平均高于对照组(P<0.001);观察组中PDGF-BB在不同肝纤维化分期两两比较差异均有统计学意义(P<0.05);TGF-β1在不同肝纤维化分期两两比较S2、S3、S4期差异无统计学意义(P>0.05),其他两两比较差异有统计学意义(P<0.05);PDGF-BB、TGF-β1与肝纤维化分期呈正相关。结论 PDGF-BB、TGF-β1在肝纤维化的早期诊断及病情评估上有重要的临床意义。

大鼠中晚期纤维化肝组织NF-κB、TGF-β1及其Ⅰ型受体表达的改变

目的 探讨肝纤维化中、晚期大鼠肝组织核转录因子 κB(NF κB)、转化生长因子 β1(TGF β1)及其Ⅰ型受体 (TβRⅠ )表达的改变。方法 采用 12 5 %CCl4诱导的大鼠肝纤维化模型 ,分别于造模的第 8、13周末处死动物 ,取左叶肝组织石蜡包埋 ,制作组织芯片 ,免疫组化S P法检测NF κBp6 5、TGF β1及TβRⅠ蛋白的表达 ,原位杂交检测TGF β1及TβRⅠmRNA的表达 ,并用MetaMorph图像分析系统对免疫组化及原位杂交结果进行定量分析。结果 第 8、13周纤维化肝组织NF κBp6 5蛋白、TGF β1及TβRⅠ蛋白和mRNA的表达均较正常组显著增强 (P <0 0 1) ,其表达相互间均呈正相关 (P<0 0 1)。结论 中晚期肝纤维化中 ,TGF β1及TβRⅠmRNA水平的增高是其蛋白表达上调的主要机制 ,NF κB、TGF β1及TβRⅠ共同作用促进肝纤维化发展。

慢性乙肝患者血清TGF-β1与肝组织病理和肝纤维组织定量的关系

目的观察血清 TGF-β1与肝组织病理和纤维定量之间的确切关系,探讨其临床应用价值.方法采用酶联免疫吸附实验(ELISA)测定76例慢性乙肝(CHB)、肝硬变(LC)患者血清 TGF-β1.30例作肝活检,进行肝组织病理学诊断,应用多媒体彩色病理图文分析系统对肝内胶原纤维、网状纤维进行定量分析.结果①CHB 轻、中、重度、LC 患者血清 TGF-β1水平(144.3μg/mL±34.1 μg/mL,349.5μg/mL±107.7μg/mL,508.3 μg/mL±133.3μg/mL,579.4 μg/mL±225.1μg/mL)明显高于对照组(95.3μg/mL±34.1 μg/mL;P<0.01).按CHB 轻、中、重度、LC 依次升高(P<0.01/0.05).②肝组织内胶原纤维、网状纤维含量随 CHB 轻、中、重度次序递增(胶原纤维的单位目标面积在肝实质为(μm^2/个):344.0±9.6,43.7±11.9,64.2±10.7;汇管区为:66.5±17.3,75.5±23.4,91.0±22.8网状纤维的单位目标面积在肝实质为(μm^2/个):11.4±5.0,17.4±4.1,26.3±9.7汇管区为:18.0±5.7,24.6±6.1,79.3±27.0 P<0.01/0.05),与血清 TGF-β1的变化一致.结论血清 TGF-β1与肝组织病理和肝组织纤维定量呈一致性改变.

缬沙坦对肝硬化患者血清血管紧张素ⅡTGF-β1的影响

目的:探讨缬沙坦对肝硬化患者血清血管紧张素Ⅱ(AngⅡ)转化生长因子-β1(TGF-β1)的影响及意义。方法:40例肝硬化患者被随机分为治疗组和对照组各20例,两组均给予常规治疗,治疗组在常规治疗基础上加用缬沙坦80mg/d,于治疗前及治疗6个月时采用ELISA法检测血清AngⅡ、TGF-β1。结果:治疗前肝硬化患者血清AngⅡ(167.84±64.81vs 51.13±15.95pg/l)及TGFβ1(181.12±32.63 vs31.46±10.39μg/l)水平均明显高于健康人,应用缬沙坦治疗后血清AngⅡ(168.67±69.03vs218.46±74.79 pg/l)较治疗前升高,而血清TGFβ1(182.22±30.60vs121.77±13.84μg/l)较治疗前下降,差异均有显著性。结论:血管紧张素ⅡⅠ型受体拮抗剂缬沙坦能降低血清TGFβ1水平,具有一定的抗纤维化作用。