Portal and Parenchymal Alterations of the Liver in Idiopathic Portal Hypertension: A Histological and Immunochemical Study
Idiopathic portal hypertension (IPH) is characterized by presinusoidal portal hypertension owing to the intrahepatic, presinusoidal portal venous block, whereas the primary cause and initial vascular lesions(s) remain only speculative. In this study, a total of 97 IPH livers were histopathologically and immunohistochemically examined, placing emphasis on hepatic parenchymal fibrosis and atrophy as well as on portal tract fibrosis. Alcoholic cirrhosis and normal livers were used as controls. When compared with normal livers, the expression of connective tissue growth factor (CTGF) in periductal mononuclear cells was significant. Matrix metalloproteinase (MMP)9-positive mononuclear cells were fewer in number in the portal tract of IPH liver, when compared with alcoholic cirrhosis. These findings suggest a possible pathogenesis of collagen and elastin deposition because of increased CTGF expression and decreased MMP-9 expression in portal tracts of IPH. Sinusoidal dilatation associated with hepatocellular atrophy and apoptosis occurred frequently, but focally in 20% of the IPH cases. These changes were most often found in hyperplastic hepatocellular areas and in the perivenular areas of hepatic lobules. In these areas, pericellular fibrosis and thin fibrous septa were also frequently seen. In these fibrotic areas, there were deposited not only collagen fibers, but also elastic fibers, in which alpha-smooth muscle actin-positive sinusoidal cells, reflecting activated hepatic stellate cells, were frequently detected. It is possible that in IPH cases, continuing portal venous blood insufficiency may be responsible for hepatic parenchymal damage, which may be followed by hepatocellular apoptotic dropout and then by hepatic parenchymal atrophy and fibrosis.
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- "Algorithms for segmentation of the fibrosis are usually threshold-based, assuming uniform staining of the fibrosis (Rubio & Porwit, 1988; Masseroli et al., 2000; Dahab et al., 2004; Friedenberg et al., 2005). The thresholds are often set manually (Rubio & Porwit, 1988; O'Brien et al., 2000; Caballero et al., 2001; Zaitoun et al., 2001; Tsuneyama et al., 2002; Dahab et al., 2004; Wyatt et al., 2004; Friedenberg et al., 2005) or based on an assumed population model (Masseroli et al., 2000). Since the perisinusoidal fibrosis and hepatocyte nuclei share the same colour space with Sirius red–stained liver sections, they are not separable in clusters. "
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ABSTRACT: Quantitation of connective tissue versus parenchymal tissue compartments is important in assessment of fibrosis (scarring) and its progression in liver disease. This paper presents a two-step algorithm for quantifying fibrosis in liver biopsies stained with Sirius red. With this staining technique, collagen and cell nuclei appear similarly stained, whereas cytoplasm appears pale. The first step of the algorithm is to separate similarly stained areas occupied by collagen and hepatocyte nuclei. Since the total area of the combined collagen and cell nuclei is usually much smaller than the remaining liver parenchyma, a non-linear intensity mapping is applied to enhance the smaller cluster in order to match the larger one in both intensity and size. The second step is to differentiate the fibrotic areas usually having irregular shapes from hepatocyte nuclei that have relatively uniform size and have circular shape. The proposed algorithm has been applied to quantify the development of progressive fibrosis and its possible regression in liver biopsy specimens from patients with parenteral-induced liver injury undergoing intestinal transplantation.
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- "Collagen a1(I) mRNA and collagen a2(I) mRNA were increased, on average, several hundred fold, as well as mRNAs encoding type V and type VIII collagens. Table 3 shows the most downregulated genes, of which MMP9 was previously reported to be downregulated in activated HSCs in vivo . To verify the microarray data we assessed the expression of the selected genes by RT-PCR. "
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ABSTRACT: Liver fibrosis is characterized by accumulation of extracellular matrix proteins synthesized by activated hepatic stellate cells (HSCs). To understand molecular mechanisms of HSCs activation a comprehensive comparison of gene expression between quiescent and activated HSCs is needed.
Using DNA microarrays we compared expression of 31,100 genes between quiescent rat HSCs and culture activated rat HSCs. Expression of the components of Wnt signaling was analyzed in HSCs and fibrotic livers by RT-PCR. Activation of beta-catenin was analyzed by Western blot.
Nine hundred genes were upregulated more than 4.6-fold and 500 genes were downregulated more than 5.7-fold in activated HSCs. The upregulated genes included Wnt receptor frizzled 2, ligands Wnt4 and Wnt5, which was confirmed in fibrotic livers. Expression of the target genes of Wnt signaling was increased from 5- to 70-fold. Phosphorylation and nuclear translocation of beta-catenin were unchanged, indicating activation of the noncanonical Wnt pathway.
Highly upregulated expression of Wnt5a and its receptor frizzled 2 implicates this pathway in differentiation of quiescent HSCs into myofibroblasts. Activation of Wnt signaling pathway in HSCs and in animal models of liver fibrosis has not been described previously, suggesting an important role of Wnt signaling in development of liver fibrosis.
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ABSTRACT: Connective tissue growth factor (CTGF/CCN2) is a highly profibrogenic molecule which is overexpressed in many fibrotic lesions, including those of the liver. CTGF/CCN2 is transcriptionally activated by transforming growth factor-beta (TGF-beta) and appears to mediate some of the extracellular matrix (ECM)-inducing properties that have been previously attributed to TGF-beta. CTGF/CCN2 and TGF-beta stimulate connective tissue cell proliferation and ECM synthesis in vitro and exhibit shared fibrogenic and angiogenic properties in vivo. In fibrotic liver, CTGF/CCN2 mRNA and protein are produced by fibroblasts, myofibroblasts, hepatic stellate cells (HSCs), endothelial cells, and bile duct epithelial cells. CTGF/CCN2 is also produced at high levels in hepatocytes during cytochrome P-4502E1-mediated ethanol oxidation. CTGF/CCN2 expression in cultured HSCs is enhanced following their activation or stimulation by TGF-beta while exogenous CTGF/CCN2 is able to promote HSC adhesion, proliferation, locomotion, and collagen production. Collectively, these data suggest that during initiating or downstream fibrogenic events in the liver, production of CTGF/CCN2 is regulated primarily by TGF-beta in one or more cell types and that CTGF/CCN2 plays important roles in HSC activation and progression of fibrosis. This article reviews the data that support the importance of CTGF/CCN2 in hepatic fibrosis and highlights the concept that CTGF/CCN2 may represent a new therapeutic target in this disease.
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