Apoptotic and survival signals in hepatic stellate cells.
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Hepatic stellate cells (HSCs) play an important role in hepatic fibrogenesis. In response to liver injury, HSCs undergo a process called activation, which involves 2 steps jonit nation from quiescent phenotype to myofibroblast-like phenotype, and perpetuation that maintains the activated phenotype of HSCs. The fate of the activated HSCs depends on the apoptotic and survival signals that they receive. The apoptosis of HSCs results from a series of complex and interrelated signaling events. Apoptotic signals for the activated HSCs include proteins from membrane receptors, such as death receptors, nerve growth factor receptor and peripheral-type benzodiazepine receptor, as well as proteins from cytoplasm such as Bcl-2 family members. The survival signals for the activated HSCs are induced by some kinases and cytokines including tissue inhibitors of metalloproteinase-1, Rho/Rho kinase, platelet-derived growth factor, transforming growth factor beta-1, and insulin-like growth factor-1. Approaches that specifically initiate HSC apoptosis are promising to be direct and effective strategies to treat liver fibrosis. Although it remains unclear whether the activated HSCs could be reversed back to the quiescent phenotype, the different expression and sensitivity of pro-apoptotic and survival molecules between quiescent and activated HSCs provide a prospect to develop therapeutic approaches that specifically targets apoptosis of the activated HSCs. These therapeutic strategies to induce HSC apoptosis are current research hotspot and the future for the patients with liver fibrosis and cirrhosis. (+info)
RNA interference targeting the platelet-derived growth factor receptor beta subunit ameliorates experimental hepatic fibrosis in rats.
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Migration of hepatic stellate cells in fibrotic microenvironment of diseased liver model.
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BACKGROUND: In liver fibrosis, alterations within the space of Disse microenvironment facilitate the progression of chronic liver disease. The normal basement membrane-like matrix in the space of Disse converts to a matrix rich in fibril-forming collagens during the fibrosis. This study aimed to investigate the impact of alterations in the space of Disse microenvironment on the migration of hepatic stellate cells (HSCs) in the process of liver fibrosis, and to explore the novel mechanism of liver fibrosis from the viewpoint of cell migration. METHODS: A modified in vitro Boyden chamber system was employed to partially mimic the in vitro microenvironment of the Disse space in normal liver and in fibrosis. The effects of fibrogenetic growth factors on the migration of HSCs in simulated liver fibrosis were assessed by cell migration and cell proliferation experiments. RESULTS: Enhanced platelet-derived growth factor (PDGF)-BB, transforming growth factor-beta1 (TGF-beta1) and/or epithelial growth factor (EGF) in liver fibrosis resulted in an increase in migratory capacity of activated HSCs. The enhanced migration of HSCs induced by PDGF-BB was proliferation-independent. The elevation of basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) during liver fibrosis had no effect on the migration of HSCs. CONCLUSIONS: The study provides valuable insights into the role of the space of Disse microenvironment in regulating the migratory behavior of HSCs. TGF-beta1, PDGF-BB and EGF, which increase in liver fibrosis, induce the migration of activated HSCs. However, bFGF and VEGF have no effect although they also increase during liver fibrosis. (+info)
AIM: To investigate the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt signaling pathway in the balance of HSC activation and apoptosis in rat hepatic stellate cells (HSC). METHODS: An activated HSC cell line was used in this study. LY 294002, the PI 3-K/Akt signal pathway blocker was used to investigate the molecular events on apoptosis in HSC and to interpret the role of this pathway in HSC apoptosis. Immunocytochemistry, Western blot and reverse transcription polymerase chain reaction (RT-PCR) analysis were applied to detect the expression of PI 3-K, and simultaneously phosphorylated-Akt (p-Akt) and total-Akt were determined by Western blot. The HSC apoptosis was examined by annexin-V/propidium iodide double-labelled flow cytometry and transmission electron microscopy. RESULTS: The apoptosis rates in LY 294002 (30.82%+/-2.90%) and LY 294002+PDGF-BB (28.16%+/-2.58%) groups were significantly increased compared with those of control (9.02%+/-1.81%) and PDGF-BB (4.35%+/-1.18%). PDGF-BB augmented PI 3-K and p-Akt expression. LY 294002 significantly reduced the contents of PI 3-K and p-Akt. mRNA transcription evaluated by RT-PCR showed similar tendencies as protein expression. CONCLUSION: Inhibition of PI 3-K/Akt signaling pathway induces apoptosis in HSC. (+info)
Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat model.
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Nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver fibrosis, progresses to cirrhosis in up to 20% of patients. We report that hepatic stellate cells (HSC) in sinusoidal lesions of liver of patients with NASH express high levels of high-affinity IL-13R (IL-13Ralpha2), which is colocalized with smooth muscle actin, whereas fatty liver and normal liver specimens do not express IL-13Ralpha2. HSCs engineered to overexpress IL-13Ralpha2 respond to IL-13 and induce TGFB1 promoter activity and TGF-beta1 production. We also developed NASH in rats by feeding a choline-deficient l-amino acid diet. These rats developed liver fibrosis as assessed by H&E staining, Masson's trichrome and Sirius red staining, and hydroxyproline assays. Treatment of these rats with IL-13R-directed cytotoxin caused a substantial decline in fibrosis and liver enzymes without organ toxicity. These studies demonstrate that functional IL-13Ralpha2 are overexpressed in activated HSCs involved in NASH and that IL-13 cytotoxin ameliorates pathological features of NASH in rat liver, indicating a novel role of this cytotoxin in potential therapy. (+info)
Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition.
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