Journal of Pathology and Translational Medicine

Original Articles

Transcriptional Regulation of Hepatic Stellate Cell Activation by siRNA for TGF-beta1.: Hoon Kyu Oh, Kyung Hyun Kim, Yoon Sup Keum, Chang Ho Cho, Jae Bok Park, Kwan Kyu Park; Korean J Pathol. 2009;43(6):503-508.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.6.503

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BACKGROUND
The cytokine-induced activation of hepatic stellate cells (HSC) plays a major role in liver fibrosis. Quiescent HSCs undergo phenotypic transformation called "transdifferentiation" in response to viral, chemical or immune insults to the liver. The cytokine TGF-beta1 plays a key role in progressive liver fibrosis. Since small interfering RNA (siRNA) is a powerful tool for silencing gene expression post-transcriptionally, the present study aimed to determine whether synthetic TGF-beta1 siRNA down-regulates the expression of the TGF-beta1 gene in immortalized and activated rat HSCs (HSC-T6s). The study examined whether synthetic TGF-beta1 siRNA prevents rat HSCs activation and extracellular matrix (ECM) production.
METHODS
TGF-beta1 siRNA or a control (pU6) siRNA was added to HSC-T6 culture media. We then performed RT-PCR and western blot analyses for TGF-beta1 and ECM components (fibronectin, type-I collagen, and TIMP-1). RESULTS: TGF-beta1 siRNA significantly down-regulated expression of TGF-beta1 mRNA and protein and attenuated mRNA and protein expressions of type-I collagen, fibronectin, and TIMP-1, as compared to the control. CONCLUSIONS: TGF-beta1 siRNA can effectively down-regulate the expression of TGF-beta1 in rat HSC, resulting in significant inhibition of HSC activation and of ECM production. These data indicate that synthetic TGF-beta1 siRNA can be a useful treatment modality to prevent liver fibrosis.

Citations

Citations to this article as recorded by

Glaucocalyxin A Attenuates the Activation of Hepatic Stellate Cells Through the TGF-β1/Smad Signaling Pathway
Zhichao Dong, Qi Gao, Hao Guo
DNA and Cell Biology.2018; 37(3): 227. CrossRef

Cellular Distribution of TGF-beta1 Peptide in Dimethylnitrosamine Induced Fibrosis of Rat Liver.: Sook Nyo Lee, Do Youn Park, Sun Kyung Lee; Korean J Pathol. 1997;31(11):1157-1165.

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Abstract: Recently attention has been focused on the biology of transforming growth factor-beta1 (TGF-beta1). TGF-beta1, a potent regulator of cell proliferation, stimulates the proliferation of many cell types of mesenchymal origin and inhibits the growth of many epithelial cells. But its cellular distribution and temporal expression remain unknown. The aim of this study was to investigate immunohistochemically the cellular distribution and temporal expression of TGF-beta1 during rat hepatic fibrosis induced by dimethylnitrosamine (DMN). At an early stage of liver fibrosis, there was evidence of multiple centrilobular hemorrhagic necrosis with parenchymal lobular collapse, and at a late stage, there was septal fibrosis with micronodule formation of the parenchyme. TGF-beta1 peptide was first expressed in centrilobular clusters of macrophage which were surrounded by many TGF-beta1 negative fat-storing cells (FSCs). Along with the progression of fibrosis, the TGF-beta1 peptide was expressed in the alpha-smooth muscle actin positive FSCs and also in some peripherally located hepatocytes of micronodules. Serum IFN-gamma was detected in the serum 2 weeks after an initial administration of DMN had reached the peak level at the 4th week and then markedly decreased at the 5th week. We think that TGF-beta1 peptide is produced by macrophages influenced by soluble IFN-gamma, and is expressed in the -smooth muscle actin positive mesenchymal cells and regenerating hepatocytes, and that this cytokine may have an important role in the synthesis of the extracellular matrix and in the regulation of hepatocytic regeneration.

Inhibitory Effect of Tetrandrine on Extracellular Matrix Deposition in Rat Hepatic Fibrosis.: Won Young Choi, Hyo Jeong Chae, Sun Kyung Lee; Korean J Pathol. 1999;33(5):319-325.

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Abstract PDF: No effective therapy has yet developed for liver fibrosis/cirrhosis by directly inhibiting the accumulation of extracellular matrix. This study was undertaken to determine the effect of tetrandrine in rat model of liver fibrosis induced by carborn tetrachloride (CCl4) administration intraorally. Tetrandrine, a calcium channel blocker, is anti-inflammatory constituent of the families Menispermaceae and Ranunculaceae, which have been used as folk remedies in China. Repeated administration of CCl4 for 14 weeks to rats induced liver fibrosis with steatosis. Rats were killed after 4, 8 or 14 weeks of treatment with CCl4, CCl4 tetrandrine (30 mg/kg) or CCl4 tetrandrine (50 mg/kg). The histopathological findings of liver were observed semi-quantitatively by light microscopy and volume percentage of the collagen deposition was determined by image analyzer. Tetrandrine inhibited collagen deposition induced by CCl4 administration, as shown by less severe steatosis and fibrosis and significantly decreased volume percentage of collagen fibers in CCl4 tetrandrine treated animals compared with CCl4 only group. Thus, the administration of tetrandrine holds great promise for treating subjects with liver fibrosis/cirrhosis as a result of chronic hepatic injury.

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