Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA141049 | ENA |
REPOSITORIES: ENA
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Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases. Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu This study compares the injury and repair processed in wild-type mice after BDL.
2011-06-09 | E-GEOD-29776 | biostudies-arrayexpress
Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases.
2011-06-09 | GSE29776 | GEO
Project description:To investigate the differential gene expression of m6A RNA methylation in cholestatic liver fibrosis, we extablished a mouse model of liver fibrosis by common bile duct ligation.
2024-12-31 | GSE218407 | GEO
Project description:STING has been identified to play a role in the onset and progression of various liver diseases.We aim to investigate whether STING mediates cholestatic liver injury. We here report that STING knockout significantly reversed cholestatic liver injury induced by bile duct ligation (BDL) and Mdr2 deficiency. Mechanistically, BDL induced the enrichment of several signaling pathways, including those associated with programmed cell death in the liver, type I interferon, innate immune response, chemotaxis, inflammation, senescence, and extracellular matrix assembly, which were significantly reversed by STING knockdown.
2025-10-01 | GSE284373 | GEO
Project description:Cholestatic liver disease encompasses any condition characterized by impaired bile flow, culminating in excessive accumulation of toxic bile acids in the liver or systemic circulation, which can lead to liver fibrosis and even progress to liver failure. There is a notable lack of accurate and effective therapeutic drugs, highlighting the urgent need for new therapeutic targets. To identify the specific liver cell type that was damaged and contributed to liver injury following bile duct ligation (BDL), primary hepatocytes (MPH), biliary epithelial cells (BECs), and Kupffer-like cells are isolated and subjected to bulk RNA-seq analysis.
2025-10-01 | GSE285689 | GEO
Project description:This experiment aims to determine the transcriptomic alteration in liver lympahtic endothelial cell (LyEC) in response to bile duct ligation (BDL)-induced cholestatic injury, which known to produce severe form of fibrosis and cirrhosis. We uncover a transcriptomic changes in LyEC associated with early-stage fibrosis/cirrhosis and late-stage decompensated liver cirrhosis. This work determines the functional change in lymphatic vessels and provides background necessary to discover therapeutic targets for improving LyEC function in the progression of liver diseases.
2024-12-31 | GSE276093 | GEO
Project description:TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs) and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype littermates were fed a diet supplemented with 1%LCA for 84 hours. Liver injury and gene expression changes induced by the LCA-diet revealed an enrichment of pathways associated with inflammation, proliferation and matrix remodelling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signalling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signalling and modulates portal pressure.
2019-11-19 | GSE139075 | GEO
Project description:Lung injury induced by common bile duct ligation in mice
| PRJNA215991 | ENA
Project description:Hepatic fibrosis, the wound-healing response to repeated liver injury, ultimately leads to cirrhosis. There is an urgent need to develop effective antifibrotic therapies. Ghrelin (encoded by Ghrl) is an orexigenic hormone that has pleiotrophic functions including protection against cell death1. Here we investigate whether ghrelin modulates liver fibrosis and protects from acute liver injury. Recombinant ghrelin reduced the fibrogenic response to prolonged bile duct ligation in rats. This effect was associated with decreased liver injury and myofibroblast accumulation as well as attenuation of the altered gene expression profile. Ghrelin also reduced fibrogenic properties in cultured hepatic stellate cells. Moreover, Ghrl-/- mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. Ghrelin also protected rat livers from acute liver injury and reduced the extent of oxidative stress and the inflammatory response. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis and hepatic expression of the ghrelin gene correlated with expression of fibrogenic genes. Finally, in patients with chronic hepatitis C, single nucleotide polymorphisms of the ghrelin gene (-994CT and â604GA) influenced the progression of liver fibrosis. We conclude that ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy. Experiment Overall Design: Rats were divided into three groups: control rats receiving saline (sham operation), rats with bile duct ligation receiving saline and rats with bile duct ligation receiving recombinant ghrelin (10 micrograms/Kg/day by a subcutaneous osmotic mimi-pump). For the microarray analysis samples from 6 rats were analyzed except for the ghrelin-treated group (5 rats).
2009-01-13 | E-GEOD-13747 | biostudies-arrayexpress
Project description:Huang-Lian-Jie-Du-Decoction, a traditional Chinese formula, has been reported to protect liver from various injuries. Two cholestasis models of rats induced by thioacetamide and by bile duct ligation were established and treated with Huang-Lian-Jie-Du-Decoction. Nuclear Magnetic Resonance-based urinary metabolic profiles were analyzed by orthogonal partial least squares discriminant analysis and univariate analysis to excavate differential metabolites associated with the injuries of the two models and the treatment effects of Huang-Lian-Jie-Du-Decoction. The two cholestatic models shared common metabolic features of excessive fatty acid oxidation, insufficient glutathione regeneration and disturbed gut flora, with specific characteristics of inhibited urea cycle and DNA damage in thioacetamide-intoxicated model, and perturbed Kreb's cycle and inhibited branched chain amino acid oxidation in bile duct ligation model. With good treatment effects, Huang-Lian-Jie-Du-Decoction could regain the balance of the disturbed metabolic status common in the two cholestasis injuries, e.g., unbalanced redox system and disturbed gut flora; and perturbed urea cycle in thioacetamide-intoxicated model and energy crisis (disturbed Kreb's cycle and oxidation of branched chain amino acid) in bile duct ligation model, respectively.
2016-06-08 | MTBLS149 | MetaboLights