慢性乙型肝炎和肝硬化患者肝组织环氧合酶-2表达与肝窦病变的关系

目的 探讨慢性乙型肝炎（CHB）和肝硬化（LC）患者肝组织环氧合酶-2表达与肝窦及窦周隙病变的关系。方法 采用免疫组化法检测了200例CHB患者肝活检组织环氧合酶-2的表达,并分析其表达变化与肝窦及窦周隙病变的关系。结果 慢性乙型肝炎和肝硬化患者的肝窦病变有狭窄、阻塞、扩张、窦周隙淤血、肝窦毛细血管化等改变。体视学研究发现肝窦数目减少,总面积、总周长和平均直径增加,与正常人存在显著性差异（P〈O．01）,与CHB轻、中度患者比,也有显著陛差异（P〈O．01）;电镜观察示肝窦内皮撕裂,基膜形成,肝窦内皮细胞出芽形成血管腔,星状细胞转化为肌成纤维细胞,COX-2表达强弱与肝窦和窦周隙病变程度呈平行关系。结论 环氧合酶-2表达增强参与了CHB患者肝窦及窦周隙病变的发病过程。     

慢性乙型肝炎患者肝组织PDGF表达与肝窦病变的关系

目的探讨慢性乙型肝炎(CHB)患者肝组织血小板衍生生长因子(PDGF)表达与肝窦病变的关系。方法采用免疫组化法检测120例CHB患者肝活检组织PDGF的表达;采用电镜技术分析CHB患者肝窦病变,并分析其表达变化与肝窦病变的关系。结果慢性乙型肝炎和肝硬化患者的肝窦病变有狭窄、阻塞、扩张、窦周隙淤血、肝窦毛细血管化等改变。PDGF的表达与病理组织学分度呈一致性改变,随着肝纤维化程度、炎症活动度和病理组织学分度的加重,PDGF在肝组织中的表达逐渐明显,且轻度与中度、重度、肝硬化组之间差异显著(P<0.01)。PDGF表达强弱与肝窦和窦周隙病变程度呈平行关系。结论PDGF表达增强可能参与了CHB患者炎症进展及肝窦和窦周隙病变的发病过程。     

慢性病毒性肝炎肝窦和 Disse腔病变与肝微循环的关系

目的 探讨慢性病毒性肝炎肝窦及Disse腔内病变与肝微循环的关系。方法 采用HE及免疫组化染色(SMA、FN、LN及Ⅳ-C),用光镜观察肝活检组织病理学及上述成份的分布,取分级诊断G1～G4、CAHC各30例,CSH10例。设正常肝5例和LC10例作对照。结果 肝窦及Disse腔病理改变有扩张、塌陷、阻塞及狭窄。肝窦塌陷等病变使有效肝窦密度随分级上升而减少,与此同时也可见众多扩张的肝窦及小静脉随分级上升而增多,在G4及CAHC尤为显著。免疫组化显示SMA分布演变尤具特征性,SMA等四种成分在肝内沉着从G1～G4和CAHC逐级增多、增粗、增浓,填塞肝窦和域Disse腔。在CAHC与LC相似。结论 肝窦塌陷等病变使有效肝窦密度减少;扩张的肝窦及小静脉是肝内“功能性捷径”,其中血流快,绕过了肝实质而进入窦后肝静脉系统;肝窦基底膜形成而毛细血管化,其后果是导致肝细胞供血不足。以上病理变化以及肌成纤维细胞的收缩特性,导致肝微循环障碍,严重影响肝细胞的存活及正常功能。     

人体肝癌中窦壁内皮细胞及基膜的病理形态学研究

目的 系统观察窦内皮细胞（ＳＥＣ）及其基膜中Ⅳ型胶原（ＣｏⅣ）及层黏素（ＬＭ）在人慢性肝病和肝细胞癌（ＨＣＣ）的病理开矿学改变。并探讨其临床病理意义。方法 对３０例人ＨＣＣ及相应癌旁组织。１０例肝硬化,５例轻度慢性肝炎和４例正常肝组织进行了ＣＤ３４、ＣｏⅣ和ＬＭ的免疫组化检测,行半定量计数,系统地观察ＳＥＣ及基膜成份在正常、慢性肝病和肝癌中的形态和数量的改变,并结合肝癌的临床病理资料进行分析。结果     

肝细胞生长因子与肝纤维化

肝细胞生长因子（ＨＧＦ）是肝细胞的强有力的增殖因子，１９８９年两个研究小组几乎同时克隆出了ＨＧＦｃＤＮＡ。以后发现ＨＧＦ的作用并不限于促进肝细胞的再生，还可以抑制肝细胞的损害，改善脂肪肝，甚至还有阻止肝纤维化的作用。因此，ＨＧＦ有望作为难治性慢性肝炎和肝硬化的治疗药物。本文介绍近年来迅速开展的有关ＨＧＦ抑制肝纤维化的分子细胞学方面的研究，并以此推测ＨＧＦ的作用机制。一、ＥＣＭ与星状细胞１９６０年在研究肝纤维化的病理组织学时，发现胶原是细胞外基质（ＥＣＭ）的主要成分，主要沉积于肝细胞与肝窦的间隙即…     

Ⅰ、Ⅳ型胶原及板层素在肝纤维化大鼠肝窦周围的变化

运用免疫组化方法检测大鼠肝脏的Ⅰ、Ⅳ型胶原及板层素（ＬＭ），发现三者在正常大鼠肝窦周围均有少量存在。在经ＣＣｌ４刺激后造成肝纤维化大鼠的肝脏，第６周造模组肝窦周围Ⅰ型胶原与正常组相似，Ⅳ型胶原明显减少，ＬＭ增多；第１１周造模组大鼠肝窦周围的Ⅰ型胶原仍无增多，Ⅳ型胶原进一步减少，ＬＭ则比第６周末明显降低。提示肝纤维化时，大鼠肝脏内皮细胞和肝细胞之间大量的功能性基底膜遭受破坏，但因连续性基底膜的形成受到干扰，肝窦毛细血管化程度不很严重，此可能是ＣＣｌ４肝纤维化大鼠有自愈倾向的原因之一。     

乙型肝炎肝窦病变的免疫组织化学及电镜观察

目的　研究乙型肝炎（ ＨＢ） 肝窦病变的免疫组化表达及超微结构变化的病理意义．方法　ＨＢ 肝活检标本３００ 例， 用ＦＮ，ＬＮ，ＣｏⅣ，αＳＭＡ 及ＶＥＧＦ 单克隆抗体作免疫组化（ＳＰ 法） 染色；另对６５ 例按照电镜技术制样，作超微结构观察．结果　ＨＢ 肝窦有狭窄、阻塞、扩张及肝窦毛细血管化４ 种病变． ＡＨＢ 以肝窦狭窄及阻塞较重者占多数（９５ ％ ） ，而ＣＨＢ 则以肝窦扩张及毛细血管化最明显，两者差异显著（ Ｐ＜ ０－０１） ．肝窦狭窄时肝细胞水肿、微绒毛断裂、线粒体畸型、窦内皮细胞增生或损伤，窗孔减少，基膜物质增多，以αＳＭＡ，ＶＥＧＦ 强表达较前者显著（ Ｐ ＜ ０－０１） ． ＦＮ ，ＬＮ，ＣｏⅣ及αＳＭＡ 表达随肝窦扩张程度升降，与ＶＥＧＦ 表达明显不同（ Ｐ＜ ０－０１） ． 肝窦内皮细胞可出芽形成管腔，基膜物质增多而ＶＥＧＦ 则下降．结论　肝窦病变免疫组化及超微结构变化与ＨＢ 演变有关．     

I,IV型胶原及板层素在肝纤维化大鼠肝窦周围的变化

运用免疫组化方法检测大鼠肝脏的Ｉ，ＩＶ型胶原及板层素（ＬＭ），发现三者在正常大鼠肝窦周围均有少量存在。在经ＣＣｌ４刺激后造成肝纤维化大鼠的肝脏，第６周造模组肝窦周围Ｉ型胶原与正常组相似，ＩＶ型胶原明显减少，ＬＭ增多，第１１周造模组大鼠肝窦周围的Ｉ型胶原仍无增多，ＩＶ型胶原进一步减少，ＬＭ则比第６周末明显降低，提示肝纤维化时，大鼠肝脏内皮细胞和肝细胞之间大量的功能性基底膜遭受破坏，但因连续性基底膜的     

慢性乙型肝炎患者血清转化生长因子β1在肝纤维化中的作用

目的 观察慢性乙型肝炎（慢乙肝）患者血清转化生长因子β１（ＴＧＦβ１）与Ⅲ型前胶原蛋白（ＰＣⅢ）、层粘连蛋白（ＬＮ）、透明质酸（ＨＡ）和肝脏纤维组织增生的关系。方法采用酶联免疫吸附试验（ＥＬＩＳＡ）测定７６例慢乙肝、肝硬化患者血清ＴＧＦβ１。２９例作肝活检，应用多媒体彩色图文分析系统进行肝内胶原纤维、网状纤维的定量分析。结果（１）慢乙肝轻、中、重度及肝硬化患者血清ＴＧＦβ１水平分别为（１４４３４±５７１）ｍｇ／Ｌ，（３４９．５３±１０７．６）ｍｇ／Ｌ，（５０８．３３±１３３．２７）ｍｇ／Ｌ，（５７９．３８±２２５．０７）ｍｇ／Ｌ，明显高于对照组（９５．３３±３４；１２）ｍｍ／Ｌ（Ｐ＜０．０１），按慢乙肝轻、中、重度、肝硬化依次升高（Ｐ＜００１或Ｐ＜０．０５）。（２）ＴＧＦβ１与血清ＰＣⅢ、ＬＮ、ＨＡ呈正相关（Ｐ＜０．０１或Ｐ＜０、０５）；血清ＴＧＦｐ１、ＰＣⅢ、ＬＮ、ＨＡ水平随着肝组织纤维化程度的加重而增长（Ｐ＜００１或Ｐ＜００５）；随着慢乙肝病情的加重，肝实质和汇管区胶原纤维、网状纤维含量逐渐增加的同时，ＴＧＦβ１亦在同步增长（Ｐ＜００１或Ｐ＜０．０５）。结论慢性乙型病毒性肝炎、肝硬化患者血清ＴＧＦβ１水平     

血清HA、PCⅢ、CⅣ及LN的水平在肝纤维化与早期肝硬化中的意义

目的　通过检测血清透明质酸（ＨＡ） 、Ⅲ型前胶原（ＰＣⅢ） 、Ⅳ型胶原（ＣⅣ） 及层粘素（ＬＮ） 的水平,了解该四项血清指标与肝纤维化及早期肝硬化的关系。方法　３６ 例慢性乙型肝炎（ 慢乙肝） 患者的血清ＨＡ、ＰＣⅢ及ＬＮ 用放免法检测（ ＲＩＡ） ;ＣⅣ用酶免法检测（ＥＩＡ） ,并与肝穿病理炎症分级（Ｇ） 和纤维化分期（Ｓ） 进行比较。结果　血清中ＨＡ、ＰＣⅢ、ＣⅣ及ＬＮ 水平与肝纤维化及早期肝硬化关系密切（ Ｐ＜ ０－０５ － ０－０１） 。结论　血清中ＨＡ、ＰＣⅢ、ＣⅣ及ＬＮ 均为较好反映肝纤维化及早期肝硬化的指标。其中ＨＡ 价值最大,ＰＣⅢ对肝脏炎症反映较好     

Significance of septal fibrosis for disturbance of hepatic circulation.

To examine the significance of fibrous septa of the liver for hepatic circulatory disturbance, haemodynamic changes were investigated in rats with septal fibrosis induced with horse serum injections. The fibrotic liver showed thin fibrous bands originating in the vicinity of the peripheral branches of the hepatic vein connected with each other and partly with the portal triads, without conspicuous periportal, pericentral or perisinusoidal fibrosis. There was no evidence of hepatic cell enlargement, disarrangement of hepatic cell plates or narrowing of the sinusoids in the fibrotic livers. Portal vascular resistance, bile production and hepatic oxygen consumption, which were measured by an isolated liver perfusion method, were much the same in the normal and the fibrotic livers. Moreover, there was no significant difference in in vivo blood pressures of the portal vein, the terminal portal venule, the terminal hepatic venule and the inferior vena cava between the normal and the fibrotic rats. These data suggest that septal fibrosis in itself does not disturb hepatic circulation.     

Significance of septal fibrosis for disturbance of hepatic circulation

Abstract: To examine the significance of fibrous septa of the liver for hepatic circulatory disturbance, haemodynamic changes were investigated in rats with septal fibrosis induced with horse serum injections. The fibrotic liver showed thin fibrous bands originating in the vicinity of the peripheral branches of the hepatic vein connected with each other and partly with the portal triads, without conspicuous periportal, pericentral or perisinusoidal fibrosis. There was no evidence of hepatic cell enlargement, disarrangement of hepatic cell plates or narrowing of the sinusoids in the fibrotic livers. Portal vascular resistance, bile production and hepatic oxygen consumption, which were measured by an isolated liver perfusion method, were much the same in the normal and the fibrotic livers. Moreover, there was no significant difference in in vivo blood pressures of the portal vein, the terminal portal venule, the terminal hepatic venule and the inferior vena cava between the normal and the fibrotic rats. These data suggest that septal fibrosis in itself does not disturb hepatic circulation.     

Appearance of alpha-smooth-muscle-actin-positive cells in hepatic fibrosis

The appearance of alpha-smooth-muscle-actin (alpha-smA)-positive cells during hepatic fibrosis was studied immunohistochemically in rat and human livers. In the normal rat liver, alpha-smA was observed only in vascular smooth muscle cells. With the progression of fibrosis induced by CCl4 injection, alpha-smA-positive cells appeared in the perisinusoidal space and the fibrous septa, and ultimately surrounded regenerative nodules. An increase of desmin-positive cells was recognized in the fibrotic areas and the perisinusoidal area. In the human liver, alpha-smA-positive cells appeared in the fibrotic area, whereas no desmin-positive cells were observed, except in vascular walls of the central vein and the portal tract, alpha-smA is a good marker for the detection of myofibroblast-like cells, and the appearance of alpha-smA in liver mesenchymal cells seems closely related to the process of hepatic fibrosis in both rat and man.     

Appearance of α-smooth-muscle-actin-positive cells in hepatic fibrosis

ABSTRACT— The appearance of α-smooth-muscle-actin (α-smA)-positive cells during hepatic fibrosis was studied immunohistochemically in rat and human livers. In the normal rat liver, α-smA was observed only in vascular smooth muscle cells. With the progression of fibrosis induced by CCl₄ injection, α-smA-positive cells appeared in the perisinusoidal space and the fibrous septa, and ultimately surrounded regenerative nodules. An increase of desmin-positive cells was recognized in the fibrotic areas and the perisinusoidal area. In the human liver, α-smA-positive cells appeared in the fibrotic area, whereas no desmin-positive cells were observed, except in vascular walls of the central vein and the portal tract. α-smA is a good marker for the detection of myofibroblast-like cells, and the appearance of α-smA in liver mesenchymal cells seems closely related to the process of hepatic fibrosis in both rat and man.     

Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis)

The pathogenesis of congestive cirrhosis is generally thought to be a reaction of the hepatic stroma to hypoxia, pressure, or necrosis. This does not explain the poor correlation between symptoms and severity of fibrosis and the irregular distribution of fibrosis within the liver. We have observed healed hepatic vein (HV) thrombosis in patients with congestive heart failure (CHF). The purposes of this study were to document hepatic vascular lesions in autopsy livers of patients with chronic CHF, to determine the role of these lesions in the pathogenesis of congestive cirrhosis, and to refine the definition of congestive cirrhosis. Twenty-five livers were studied, 13 with multiple large blocks 4 × 5 cm. Sections were graded for parenchymal fibrous septa, sinusoidal fibrosis, and intimal fibrosis of portal veins (PVs) and HVs. Fibrous septa were found in livers of 7 of 13 patients with CHF and in none of 12 controls without CHF (P = .007). Parenchymal fibrosis was highly variable in distribution, often with severe septation in some areas and nearly normal morphology in others. Intimal fibrosis and obstruction of small- and mediumHVs were found only in livers of patients with CHF. The vascular lesions were confined to regions with fibrous septation and had morphology suggestive of organized thrombosis. Acute thrombi in sinusoids were noted in livers of 4 patients with CHF and in livers of 2 patients without CHF. These findings support the hypothesis that congestive cirrhosis is a response to intrahepatic thrombosis. The pattern of disease suggests that thrombus begins in sinusoids, occasionally propagates to HVs, and causes secondary local PV thrombosis, ischemia, parenchymal extinction, and fibrosis.     

Morphological and serum hyaluronic acid, laminin and type IV collagen changes in dimethylnitrosamine-induced hepatic fibrosis of rats

AIM: To study the morphological and serum hyaluronic acid (HA), laminin (LN), and type IV collagen changes in hepatic fibrosis of rats induced by dimethylnitrosamine (DMN). METHODS: The rat model of liver fibrosis was induced by DMN. Serum HA, type IV collagen, and LN were measured by ELISA. The liver/weight index and morphological changes were examined under electron microscope on d 7, 14, 21, and 28 by immunohistochemical alpha smooth muscle actin alpha-SMA staining as well as Sirius-red and HE staining. RESULTS: The levels of serum HA, type IV collagen and LN significantly increased from d 7 to d 28 (P = 0.043). The liver/weight index increased on d 7 and decreased on d 28. In the model group, the rat liver stained with HE and Sirius-red showed evident hemorrhage and necrosis in the central vein of hepatic 10 lobules on d 7. Thin fibrotic septa were formed joining central areas of the liver on d 14. The number of alpha-SMA positive cells was markedly increased in the model group. Transitional hepatic stellate cells were observed under electron microscope. All rats in the model group showed micronodular fibrosis in the hepatic parenchyma and a network of alpha-SMA positive cells. Typical myofibroblasts were embedded in the core of a fibrous septum. Compared to the control group, the area-density percentage of collagen fibrosis and pathologic grading were significantly different in the model group (P<0.05) on different d (7, 14, and 28). The area-density percentage of collagen fibrosis in hepatic tissue had a positive correlation with the levels of serum HA, LN, and type IV collagen. CONCLUSION: The morphological and serum HA, type IV collagen, and LN are changed in DMN-induced liver fibrosis in rats.     

Morphological and serum hyaluronic acid, laminin and type Ⅳ collagen changes in dimethylnitrosamine-induced hepatic fibrosis of rats

AIM: To study the morphological and serum hyaluronic acid (HA), laminin (LN), and type Ⅳ collagen changes in hepatic fibrosis of rats induced by dimethylnitrosamine (DMN).METHODS: The rat model of liver fibrosis was induced by DMN. Serum HA, type Ⅳ collagen, and LN were measured by ELISA. The liver/weight index and morphological changes were examined under electron microscope on d 7, 14, 21, and 28 by immunohistochemical alpha smooth muscle actin α-SMA staining as well as Sirius-red and HE staining.RESUJLTS: The levels of serum HA, type Ⅳ collagen and LN significantly increased from d 7 to d 28 (P = 0.043).The liver/weight index increased on d 7 and decreased on d 28. In the model group, the rat liver stained with HE and Sirius-red showed evident hemorrhage and necrosis in the central vein of hepatic 10 lobules on d 7. Thin fibrotic septa were formed joining central areas of the liver on d 14. The number of α-SMA positive cells was markedly increased in the model group. Transitional hepatic stellate cells were observed under electron microscope.All rats in the model group showed micronodular fibrosis in the hepatic parenchyma and a network of α-SMA positive cells. Typical myofibroblasts were embedded in the core of a fibrous septum. Compared to the control group, the area-density percentage of collagen fibrosis and pathologic grading were significantly different in the model group (P＜0.05) on different d (7, 14, and 28). The area-density percentage of collagen fibrosis in hepatic tissue had a positive correlation with the levels of serum HA, LN, and type Ⅳ collagen.CONCLUSION: The morphological and serum HA, type Ⅳ collagen, and LN are changed in DMN-induced liver fibrosis in rats.     

Sinusoidal portal hypertension in hepatic amyloidosis.

Hepatic venous catheterisation and transvenous liver biopsy were performed in five patients with hepatic amyloidosis. In three patients, hepatic venous pressures were normal and histological examination of the liver biopsy specimen showed discrete and sparse perisinusoidal amyloid deposits. In the other two, however, the gradient between wedged and free hepatic venous pressures was increased (12 and 16 mmHg; normal 1-4 mmHg) and amyloid deposits were abundant and diffuse in the Disse's space. This study shows that portal hypertension in patients with hepatic amyloidosis is of the sinusoidal type and is related to the reduction of vascular space of hepatic sinusoids by massive perisinusoidal amyloid deposits. Furthermore, portal hypertension is associated with a poor prognosis in patients with hepatic amyloidosis.     

Hepatic content of collagens and laminin in rat model of experimental liverfibrosis

AIM The hepatic content of collagens (type I, Ⅲ and Ⅶ) and laminin (LN) in rat model of experimentalliver fibrosis was observed to find out their roles in the pathogenesis of liver fibrosis.METHODS The experimental rat model was established by immunological injury induced by injectinghuman albumin. Histopathological and immunohistochemical methods were used to measure the hepaticcontent of collagens and laminin in the fibrotic rat livers.RESULTS The hepatic contents of collagens (type I, Ⅲ, Ⅶ) and LN in the fibrotic rat livers weresignificantly increased as compared with those in the control group, and they were found to be mainlylocalized in the portal space, central veins and fibrous septa. Electron microscopic study showed that pro-collagens were present around the “activated” hepatic stellate cells (HSC) and the hepatocytes atrophied.CONCLUSION Pathological deposition of collagens (type Ⅰ, Ⅲ and Ⅶ ) and laminin was the fundamentallesion of liver fibrosis. HSC may be the major cellular source of collagens (type Ⅰ, Ⅲ and Ⅶ) and laminin inthe liver tissue.     

Diffuse expression of heparan sulfate proteoglycan and connective tissue growth factor in fibrous septa with many mast cells relate to unresolving hepatic fibrosis of congenital hepatic fibrosis.

BACKGROUND AND AIMS: Congenital hepatic fibrosis (CHF) is characterized by dense portal/septal fibrosis and bile duct proliferation and tortuosity. In this study, the roles and significance of fibrosis-related cells and molecules in the process of progressive and unresolving fibrosis of CHF were examined in comparison with other fibrotic liver diseases. METHODS: Seven CHF livers were examined, and a total of 74 control livers (chronic viral hepatitis (CVH), alcoholic fibrosis/cirrhosis (F/C), extrahepatic biliary obstruction and livers showing non-specific reactive changes) were used as controls. All of these livers were wedge biopsied or surgically resected ones, and were formalin fixed and paraffin embedded. In addition to histologic observations, expression of heparan sulfate proteoglycan (HSPG), connective tissue growth factor (CTGF), mast cell-specific tryptase, alpha-smooth muscle actin for activated hepatic stellate cells (HSC) or myofibroblasts (MF) were immunohistochemically surveyed. HSPG and CTGF at mRNA were also examined by in situ hybridization. RESULTS: Portal/septal fibrosis of CHF were mature collagenous and elastic fiber poor, when compared with controls. HSPG and CTGF were diffusely abundant in fibrous portal tracts/septa in CHF, while they were more or less accentuated at periportal areas in alcoholic F/C and CVH. In CHF, the number of interface and portal/septal MF was increased from mild-to-moderate degree, while their increase was moderate to marked in alcoholic F/C and CVH, particularly F3/F4. While activated HSC were frequent in alcoholic F/C and CVH and they were continuous with interface MF, activated HSC in CHF were scanty. Instead, mast cells were increased in portal/septal fibrosis of CHF. Portal mononuclear cells and endothelial cells were positive for HSPG mRNA, and mononuclear cells for CTGF mRNA, and such cells were accentuated around proliferated bile ducts and ductules in CHF. CONCLUSIONS: Abundant CTGF retained diffusely in HSPG in the fibrous portal tracts/septa may be responsible for non-resolving hepatic fibrosis in CHF, and many mast cells and portal MF not related to HSC may causally relate to such characteristic finding in CHF.