MicroRNA-29a Alleviates Bile Duct Ligation Exacerbation of Hepatic Fibrosis in Mice through Epigenetic Control of Methyltransferases

Hepatic fibrosis or increased liver collagen contents drive functional abnormalities that, when extensive, may be life threatening. The purpose of this study was to assess the effects of the chronic stimulation or inhibition of nitric oxide synthesis in rats with hepatic fibrosis induced by permanent common bile duct ligation (3 weeks) and the role of expression of the different nitric oxide synthase isoforms. Bile duct ligation led to an important accumulation of collagen in the hepatic parenchyma, as shown both histologically and by the hydroxyproline contents of livers. Bilirubin and serum enzyme activities (measured as markers of cholestasis) increased several-fold after bile duct ligation. The area of fibrotic tissue, liver hydroxyproline content and serum markers of cholestasis were clearly related in obstructed rats. The absence of modifications in haemodynamic parameters excludes circulatory changes from being responsible for the development of liver alterations. In animals treated with NG-nitro-L-arginine methyl ester (L-NAME) the area of fibrosis was similar to that of untreated animals, the signs of cholestasis and cellular injury being more evident. In rats treated with L-arginine the area of fibrosis was almost three times larger than that found in bile duct ligated rats and in L-NAME-treated bile duct ligated rats, although the observed biochemical changes were similar to those seen in rats treated with L-NAME. Our results with inducible nitric oxide synthase, obtained by Western blots and immunohistochemistry, indicate a greater expression of the inducible enzyme in bile duct ligated and L-arginine-treated animals and a lower expression in the L-NAME and control groups. Constitutive nitric oxide synthase expression, obtained by Western blots, was very similar in all groups, except for the L-arginine-treated rats in which it was lower. These results suggest that nitric oxide production may be a key factor in the development of fibrosis in bile duct ligated rats. They also support the hypothesis of a dual role for nitric oxide; one beneficial, mediated by its circulatory effects, and the second negative, through its local toxic effects.

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[335] THE ANTI-FIBROTIC EFFECTS OF CELECOXIB IN BILE DUCT LIGATION- AND THIOACETAMIDE-INDUCED HEPATIC FIBROSIS MODELS IN RAT

Journal of Hepatology ◽

10.1016/s0168-8278(07)61933-3 ◽

2007 ◽

Vol 46 ◽

pp. S131

Author(s):

Y.H. Paik ◽

S.H. Kang ◽

H.J. Lee ◽

S.H. Ahn ◽

K.H. Han ◽

...

Keyword(s):

Bile Duct ◽

Hepatic Fibrosis ◽

Bile Duct Ligation ◽

Duct Ligation

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The effects of the selective mineralocorticoid receptor antagonist eplerenone on hepatic fibrosis induced by bile duct ligation in rat

International Journal of Molecular Medicine ◽

10.3892/ijmm_00000417 ◽

2010 ◽

Vol 25 (6) ◽

Author(s):

Koda

Keyword(s):

Bile Duct ◽

Receptor Antagonist ◽

Hepatic Fibrosis ◽

Mineralocorticoid Receptor ◽

Bile Duct Ligation ◽

Mineralocorticoid Receptor Antagonist ◽

Duct Ligation

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M1567 CpG Motifs Induce Proinflammatory Events in Hepatic Stellate Cells and Are Involved in Bile Duct Ligation-Induced Hepatic Fibrosis In Vivo

Gastroenterology ◽

10.1016/s0016-5085(08)63714-2 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-795

Author(s):

Erwin Gäbele ◽

Matthias Froh ◽

Reiner Wiest ◽

Florian Obermeier ◽

Jürgen Schölmerich ◽

...

Keyword(s):

Bile Duct ◽

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Bile Duct Ligation ◽

Stellate Cells ◽

Cpg Motifs ◽

Duct Ligation

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Early colchicine administration reduces hepatic fibrosis and portal hypertension in rats with bile duct ligation

Journal of Hepatology ◽

10.1016/s0168-8278(05)80181-3 ◽

1993 ◽

Vol 19 (1) ◽

pp. 90-94 ◽

Cited By ~ 26

Author(s):

Jorge L. Poo ◽

Gérard Feldmann ◽

Alain Moreau ◽

Christophe Gaudin ◽

Didier Lebrec

Keyword(s):

Portal Hypertension ◽

Bile Duct ◽

Hepatic Fibrosis ◽

Bile Duct Ligation ◽

Duct Ligation

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Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation

Clinical Science ◽

10.1042/cs19980250 ◽

1999 ◽

Vol 96 (3) ◽

pp. 297 ◽

Cited By ~ 20

Author(s):

Paula MAYORAL ◽

Manuela CRIADO ◽

Froilan HIDALGO ◽

Olga FLORES ◽

Miguel A. ARÉVALO ◽

...

Keyword(s):

Nitric Oxide ◽

Bile Duct ◽

Hepatic Fibrosis ◽

Bile Duct Ligation ◽

Duct Ligation

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Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation

Journal of Hepatology ◽

10.1016/s0168-8278(97)80473-4 ◽

1997 ◽

Vol 26 (6) ◽

pp. 1363-1371 ◽

Cited By ~ 42

Author(s):

Frédéric Oberti ◽

Christophe Pilette ◽

Hervé Rifflet ◽

Moussa Y. Maïga ◽

Alain Moreau ◽

...

Keyword(s):

Portal Hypertension ◽

Bile Duct ◽

Hepatic Fibrosis ◽

Bile Duct Ligation ◽

Duct Ligation

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LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00405.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. G1318-G1328 ◽

Cited By ~ 83

Author(s):

Fuyumi Isayama ◽

Ian N. Hines ◽

Michael Kremer ◽

Richard J. Milton ◽

Christy L. Byrd ◽

...

Keyword(s):

Bile Duct ◽

Liver Fibrosis ◽

Liver Injury ◽

Hepatic Fibrosis ◽

Bile Duct Ligation ◽

Wild Type ◽

Hepatic Macrophages ◽

Duct Ligation ◽

Lps Signaling ◽

Experimental Cholestasis

Although it is clear that bile acid accumulation is the major initiator of fibrosis caused by cholestatic liver disease, endotoxemia is a common side effect. However, the depletion of hepatic macrophages with gadolinium chloride blunts hepatic fibrosis. Because endotoxin is a key activator of hepatic macrophages, this study was designed to test the hypothesis that LPS signaling through CD14 contributes to hepatic fibrosis caused by experimental cholestasis. Wild-type mice and CD14 knockout mice (CD14−/−) underwent sham operation or bile duct ligation and were killed 3 wk later. Measures of liver injury, such as focal necrosis, biliary cell proliferation, and inflammatory cell influx, were not significantly different among the strains 3 wk after bile duct ligation. Markers of liver fibrosis such as Sirius red staining, liver hydroxyproline, and α-smooth muscle actin expression were blunted in CD14−/− mice compared with wild-type mice after bile duct ligation. Despite no difference in lymphocyte infiltration, the macrophage/monocyte activation marker OX42 (CD11b) and the oxidative stress/lipid peroxidation marker 4-hydroxynonenal were significantly upregulated in wild-type mice after bile duct ligation but not in CD14−/− mice. Increased profibrogenic cytokine mRNA expression in the liver after bile duct ligation was significantly blunted in CD14−/− mice compared with the wild type. The hypothesis that LPS was involved in experimental cholestatic liver fibrosis was tested using mice deficient in LPS-binding protein (LBP−/−). LBP−/− mice had less liver injury and fibrosis (Siruis red staining and hydroxyproline content) compared with wild-type mice after bile duct ligation. In conclusion, these data demonstrate that endotoxin in a CD14-dependent manner exacerbates hepatic fibrogenesis and macrophage activation to produce oxidants and cytokines after bile duct ligation.

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Carvedilol Attenuates the Progression of Hepatic Fibrosis Induced by Bile Duct Ligation

BioMed Research International ◽

10.1155/2017/4612769 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Xiaopeng Tian ◽

Chunhong Zhao ◽

Jinbo Guo ◽

Shurui Xie ◽

Fengrong Yin ◽

...

Keyword(s):

Oxidative Stress ◽

Bile Duct ◽

Hepatic Fibrosis ◽

Transforming Growth Factor ◽

Bile Duct Ligation ◽

Antioxidant Properties ◽

Dependent Manner ◽

Sod Activity ◽

Duct Ligation ◽

Clinical Benefits

Background.The sympathetic nervous system (SNS) is responsible for hepatic stellate cells (HSCs) activation and the accumulation of collagen that occurs in hepatic fibrogenesis. Carvedilol has been widely used for the complication of hepatic cirrhosis in the clinic. Furthermore, it has powerful antioxidant properties. We assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may further enhance its clinical benefits.Methods.Using a bile duct ligation rat model of hepatic fibrosis, we studied the effects of carvedilol on the fibrosis, collagen deposition, and oxidative stress based on histology, immunohistochemistry, western blot, and RT-PCR analyses.Results.Carvedilol attenuated liver fibrosis, as evidenced by reduced hydroxyproline content and the accumulation of collagen, downregulated TIMP-1 and TIMP-2, and upregulated MMP-13. MMP-2 was an exception, which was decreased after carvedilol treatment for 2 weeks and upregulated after carvedilol treatment for 4 weeks. Carvedilol reduced the activation of HSCs, decreased the induction of collagen, transforming growth factor-β1, and MDA content, and strengthened the SOD activity. The antifibrotic effects were augmented as dosages increased.Conclusions.The study indicates that carvedilol attenuated hepatic fibrosis in a dose-dependent manner. It can decrease collagen accumulation and HSCs activation by the amelioration of oxidative stress.

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