Effect of rosiglitazone on metalloproteinase tissue inhibitor-1 in CCl_4-induced liver fibrosis in rats
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Liver fibrosis results from chronic injury followed by activation of macrophages and fibrogenic cells like myofibroblasts and activated hepatic stellate cells. These fibrogenic cells express α-smooth muscle actin (α-SMA) and produce excessive extracellular matrix (ECM), with disorganization and loss of function of hepatic parenchyma. It is known that increased levels of metalloproteinases (MMPs) in liver fibrosis are associated with reduction of the pathologic ECM and fibrosis resolution. Recently, it has been shown that bone marrow mononuclear cells (BMMNCs) may reduce collagen and α-SMA expression, and ameliorate liver function in cholestatic rats. Therefore, this study aimed to analyze MMP-2, MMP-9 and MMP-13, and tissue inhibitors of MMPs (TIMPs)-1 and TIMP-2 in the liver of cholestatic rats transplanted with BMMNC. Animals were divided into normal rats, cholestatic rats obtained after 14 and 21 days of bile duct ligation (BDL), and rats obtained after 14 days of BDL that received BMMNCs and were killed after 7 days. MMP and TIMP expression was assessed by Western blotting, along with α-SMA, CD68 and CD11b expression by confocal microscopy. Western blotting analysis showed that 14-day BDL animals had significantly reduced amounts of MMP-2 and MMP-13, but increased amounts of MMP-9 compared to normal rats. After 21 days of BDL, overall MMP amounts were decreased and TIMPs were increased. BMMNC transplantation significantly increased MMP-9 and MMP-13, and decreased TIMP expression. Increased MMP activity was confirmed by zymography. MMP-9 and MMP-13 were expressed by macrophages near fibrotic septa, suggesting BMMNC may stimulate MMP production in fibrotic livers, contributing to ECM degradation and hepatic regeneration.
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Objective To investigate the effects of Rosiglitazone on expressions of MMP-2 and TIMP-1 mRNA in hepatic stellate cells(HSCs) in vitro.Methods The HSC line,HSC-T6 was incubated with different concentrations of Rosiglitazone.The MMP-2 and TIMP-1 mRNA levels were measured by reverse-transcription polymerase chain reaction(RT-PCR).Results Expression of TIMP-1 mRNA in the Rosiglitazone-treatment groups was significantly lower than that in the control group(P0.05),and there was no difference in the MMP-2 mRNA levels between the Rosiglitazone-treatment groups and the control group.Conclusion The anti-fibrosis mechanism of Rosiglitazone is partly due to its down-regulation on TIMP-1 but not on MMP-2 expression of hepatic stellate cells.
Rosiglitazone
Hepatic stellate cell
Hepatic fibrosis
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Liuweiwuling tablets (LWWL) are an herbal product that exerts remarkable effects on liver protection and aminotransferase levels, and they have been approved by the Chinese State Food and Drug Administration (CFDA). Clinical studies have found that LWWL can inhibit collagen production and reduce the levels of liver fibrosis markers in the serum. Thus, LWWL is expected to have beneficial effects in the treatment of liver fibrosis. The purpose of this study was to evaluate the pharmacological effects of LWWL. Hepatic fibrosis was induced in rats via carbon tetrachloride (CCl4) treatment. The rats were treated twice weekly for 8 weeks with either 2 mL·kg− 1 body weight of a 50% solution of CCl4 in olive oil or olive oil alone by oral gavage. A subset of rats received daily intraperitoneal injections of either colchicine (0.2 mg/kg per day), LWWL (0.4, 1.6, or 6.4 g/kg per day), or vehicle (N = 12 for all groups) during weeks 9–12. The rats were sacrificed after 12 weeks. Pathological changes in hepatic tissue were examined using hematoxylin and eosin (H&E) and Sirius Red staining. Immunohistochemistry was performed to observe α-smooth muscle actin (α-SMA) and collagen type I (collagen I) protein expression. Western blotting was also used to detect α-SMA protein expression. Real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) was used to detect transforming growth factor-1 (TGF-β1), platelet-derived growth factor (PDGF), tissue inhibitor of metalloproteinase-1 (TIMP1), and tissue inhibitor of metalloproteinase-2 (TIMP2) mRNA expression. LWWL significantly reversed histological fibrosis and liver injury, reduced the hydroxyproline content in liver tissue, and decreased α-SMA and collagen I expression. LWWL also suppressed hepatic stellate cell (HSC) activation by reducing the expression of the profibrogenic factors TGF-β1 and PDGF. The expression levels of TIMP1 and TIMP2, which regulate extracellular matrix (ECM) degradation, were decreased after CCl4 injury in LWWL-treated rats. These data suggest that LWWL may serve as a promising therapeutic agent to reduce fibrogenesis.
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Conference Abstract| December 01 1994 Tissue Inhibitor of Metalloproteinase-1 is Expressed by Hepatic Lipocytes and Upregulated in Cirrhosis and CCl4-Induced Liver JP Iredale; JP Iredale 1University Medicine, Southampton General Hospital, Southampton, United Kingdom Search for other works by this author on: This Site PubMed Google Scholar WF Ferris; WF Ferris 1University Medicine, Southampton General Hospital, Southampton, United Kingdom Search for other works by this author on: This Site PubMed Google Scholar G Murphy; G Murphy *Strangeways Research Laboratory, Cambridge, United Kingdom Search for other works by this author on: This Site PubMed Google Scholar Mjp Arthur Mjp Arthur 1University Medicine, Southampton General Hospital, Southampton, United Kingdom Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1994) 87 (s31): 34P. https://doi.org/10.1042/cs045034P_pt2 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation JP Iredale, WF Ferris, G Murphy, Mjp Arthur; Tissue Inhibitor of Metalloproteinase-1 is Expressed by Hepatic Lipocytes and Upregulated in Cirrhosis and CCl4-Induced Liver. Clin Sci (Lond) 1 December 1994; 87 (s31): 34P. doi: https://doi.org/10.1042/cs045034P_pt2 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu nav search search input Search input auto suggest search filter All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1994 The Biochemical Society and the Medical Research Society1994 Article PDF first page preview Close Modal You do not currently have access to this content.
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CCL4
HMGB1
Hepatic fibrosis
Hepatic stellate cell
Liver function
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Liver fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSC), which proliferate during fibrotic liver injury. We have studied a model of spontaneous recovery from liver fibrosis to determine the biological mechanisms mediating resolution. Livers were harvested from rats at 0, 3, 7, and 28 d of spontaneous recovery from liver fibrosis induced by 4 wk of twice weekly intraperitoneal injections with CCl4. Hydroxyproline analysis and histology of liver sections indicated that the advanced septal fibrosis observed at time 0 (peak fibrosis) was remodeled over 28 d of recovery to levels close to control (untreated liver). alpha-Smooth muscle actin staining of liver sections demonstrated a 12-fold reduction in the number of activated HSC over the same time period with evidence of HSC apoptosis. Ribonuclease protection analysis of liver RNA extracted at each recovery time point demonstrated a rapid decrease in expression of the collagenase inhibitors TIMP-1 and TIMP-2, whereas collagenase mRNA expression remained at levels comparable to peak fibrosis. Collagenase activity in liver homogenates increased through recovery. We suggest that apoptosis of activated HSC may vitally contribute to resolution of fibrosis by acting as a mechanism for removing the cell population responsible for both producing fibrotic neomatrix and protecting this matrix from degradation via their production of TIMPs.
Hepatic stellate cell
Hepatic fibrosis
Hydroxyproline
Interstitial collagenase
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Hepatic stellate cell
TIMP1
Hepatic fibrosis
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Type I collagen
Hepatic fibrosis
Matrix (chemical analysis)
Hepatic stellate cell
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To evaluate the effect of genistein on the fibrosis and matrix degradation caused by experimentally induced fibrosis in rats.Hepatic fibrosis was brought about by chronic administration of carbon tetrachloride to rats. To evaluate the effect of genistein on liver fibrosis and function, total collagen content and proteolytic activity in the liver were quantified. Urokinase-type plasminogen activator (uPA) expression during experimental fibrosis was localized by immunohistochemistry. Histopathological changes were evaluated using light and electron microscopy.Animals with fibrosis and treated with genistein showed an important reduction (73%) in hepatic collagen content as well as an improvement in liver function (p < 0.001). Genistein increased the capacity of the liver to degrade type I collagen and Matrigel (3.1- and 3.7-fold, respectively; p < 0.001) in animals with liver fibrosis. Genistein increased the number of uPA-immunoreactive cells. The increase in the uPA expression correlated with an increase in proteolytic activity. Histological analysis revealed a reduction in the number of fiber septa in pericentral and perisinusoidal areas. Transmission electron micrographs of livers from animals with fibrosis and treated with genistein showed a reduction in the number of hepatic stellate cells activated and a smaller number of collagen fibers.Genistein is able to improve the liver after injury and fibrosis induced by chronic administration of carbon tetrachloride. This finding suggests that genistein has antifibrogenic potential and could therefore be useful for treating chronic liver disease.
Hepatic stellate cell
Hepatic fibrosis
Thioacetamide
CCL4
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