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  • br Introduction Liver fibrosis cirrhosis is

    2019-06-12


    Introduction Liver fibrosis/cirrhosis is a global health problem that leads to morbidity and mortality. Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in western developed countries and accounts for more than 50% of cirrhosis cases. Alcoholic liver fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) in the liver. While liver fibrosis is reversible and treatable in the initial stage, it becomes irreversible and untreatable in its advanced stages. Hepatic stellate SC 144 (HSCs) play a key role in fibrogenesis and are responsible for the production of the ECM. It is known that the transdifferentiation of quiescent HSCs to myofibroblast-like cells is a hallmark of liver fibrogenesis. ECM secretion is significantly increased upon activation of HSCs. These conditions lead to liver fibrosis accompanied by enhanced HSC migration. HSC activation is divided into two stages: initiation and perpetuation. The initiation stage involves changes in gene expression and phenotypes. Sustained stimulation of HSCs over a long term results in the perpetuation stage that involves proliferation and fibrogenesis. After activation, HSCs become more contractile, proinflammatory, and fibrogenic. Additionally, after transdifferentiation, activated HSCs migrate to injury sites where they produce >50-fold higher levels of ECM in which type I collagen is the major component. The excessive collagen accumulation in activated HSC is mainly due to the enhanced stability of type I collagen mRNA. In our previous study, HSC-T6 cells exposed to alcohol for 48 h demonstrated enhanced αCP2 expression leading to the prolonged stability of type I collagen mRNA. In a fibrotic microenvironment, various cytokines including transforming growth factor β1 (TGF-β1), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) play major roles in stimulating fibrosis and cirrhosis. These cytokines promote cell proliferation and migration as well as excessive collagen production. TGF-β1, one of the most potent profibrogenic cytokines, is involved in the initiation and maintenance of fibrogenesis. TGF-β1-stimulated activation of HSCs is reported to be the key fibrogenic response in liver fibrosis. In addition, PDGF, an important cytokine, promotes collagen production upon HSC activation. PDGF and its receptor (PDGFR) are up-regulated after HSC activation and correlate with the degree of fibrosis. EGF plays a critical role in liver regeneration and HSC transdifferentiation. EGF and EGF receptor are highly overexpressed in fibrotic livers, resulting in an increased HSC migratory capacity and upregulated matrix metalloproteinase-2 activity.
    Materials and methods
    Results
    Discussion In our previous study, we demonstrated that a synthetic PCBP2 siRNA has a potent silencing effect on the expression of αCP2 that stabilizes type I collagen α1 mRNA in activated HSCs. As an activated HSC line, HSC-T6 cells reflect a fibroblast-like phenotype that proliferates rapidly in culture. HSC-T6 cells express cytoskeletal proteins, such as desmin, alpha-smooth muscle actin, glial acidic fibrillary protein, and vimentin, which are typical markers of activated stellate cells. In the current study, primary HSCs isolated from normal rats were stimulated with alcohol and cytokines. This model was used to mimic the activation of quiescent HSCs in the initiation stage of fibrogenesis. We also used HSC-T6 cells as a model of the perpetuation stage of fibrogenesis. HSCs are the main contributor to ECM accumulation in the development of alcoholic liver fibrosis. HSCs transdifferentiate into active fibroblasts after continuous exposure to alcohol or other chronic injuries. An increase in cytokine release has been reported to occur during the chronic wound-healing process. The activated fibroblasts migrate to injury sites where they demonstrate enhanced proliferation and collagen production. In our previous study, we found overexpression of αCP2 and collagen type I in HSC-T6 cells after exposure to alcohol, and the PCBP2 siRNA reverses the collagen accumulation in HSC-T6 cells.