Mouse models of acute and chronic liver damage
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ABSTRACT:
PROVIDER: PRJNA702143 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13762619_1.fastq.gz | Fastqsanger.gz | |||
| SRR13762619_2.fastq.gz | Fastqsanger.gz | |||
| SRR13762620_1.fastq.gz | Fastqsanger.gz | |||
| SRR13762620_2.fastq.gz | Fastqsanger.gz | |||
| SRR13762621_1.fastq.gz | Fastqsanger.gz |
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Project description:TGFβ/BMP family member Bone Morphogenetic Protein 8b (Bmp8b) is upregulated in NASH (Western Diet -WD- Model), acute liver damage (CCl4 model) and by Partial Hepatectomy (PH). Absence of Bmp8b reduces liver inflammation and fibrosis in the NASH model (WD). In the acute (3days) CCl4 model, absence of Bmp8b impacts acute inflammatory responses, hepatic stellate cells (HSC) activation, and compensatory hepatocyte proliferation; defective inflammatory pathways and hepatocytes proliferation is also observed in the Partial hepatectomy model. BMP8b is thus a pathophysiologically relevant target to modulate the responses to damage in acute and chronic liver disease.
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Project description:Molecular characterization of chronic liver disease dynamics: from liver fibrosis to acute-on-chronic liver failure
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Project description:Background and aims: Liver is a major target organ for alcohol-induced disease and the spectrum of pathological states elicited by alcohol in liver comprises steatosis, alcoholic steatohepatitis, progressive fibrosis and cirrhosis, conditions that may progress to hepatocellular carcinoma. Many experimental animal models of alcoholic steatohepatitis exist that vary in duration, mode of alcohol administration and the degree and types of liver injury produced. While most of these models, regardless whether alcohol is administered through liquid diet or intragastrically, produce steatohepatitis and mild fibrosis, it is widely acknowledged that these models fail to fully recapitulate key characteristics of severe forms of alcoholic liver disease, such as alcoholic hepatitis. Recent studies attempted to combine alcohol and fibrosis and achieved promising results in mouse models that achieve some of the key features of alcoholic liver disease accompanied by exacerbated fibrosis and acute renal injury. This study combined a chronic cholestatic liver fibrosis model induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) with a mouse model of intragastric alcohol feeding. Methods: Adult male C57BL6/J mice were treated with 3,5-diethoxycarbonyl-1,4-dihydrocolidine (DDC) containing diet (0.05% w/w) to induce chronic liver fibrosis. Following DDC-induced fibrogenesis, ethyl alcohol (EtOH) (up to 27 g/ kg/day, up to 28 days) was administered continuously to mice via a gastric feeding tube (Tsukamoto-Frenchmodel of alcoholic liver disease). Results: Exposure to DDC or EtOH alone resulted in liver fibrosis or steatosis, respectively. Combined treatment with DDC and EtOH lead to an additive effect on liver injury, as evident by the development of hepatic inflammation, steatosis, and pericellular fibrosis, and by increased serum transaminase levels, compared to mice treated with either agent alone. Liver transcriptomic changes specific to combined treatment group included pathways involved in the cell cycle and DNA damage. Analyses of feces from these mice revealed alcohol-associated changes to the bile acid profile and gut microbiome. Conclusions: Mice treated with DDC and EtOH displayed several key characteristics of human alcoholic hepatitis, including pericellular fibrosis, increased hepatic bacterial load with dysbiosis, reduced capacity of the microbiome to synthesize secondary bile acids.
2018-09-14 | GSE119953 | GEO
Project description:Animal model of acute-on-chronic alcoholic liver injury
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Project description:Immune-mediated liver damage is the driver of disease progression in patients with chronic Hepatitis B virus (HBV) infection. Liver damage is an antigen-independent process caused by bystander activation of CD8 T cells and NK cells. How bystander lymphocyte activation is initiated in chronic hepatitis B (CHB) patients remains unclear. Periods of liver damage, called hepatic flares, occur unpredictably, making early events difficult to capture. To address this obstacle, we longitudinally sampled the liver of CHB patients stopping antiviral therapy and analyzed immune composition and activation using flow cytometry and single-cell RNA sequencing (scRNA-seq). At 4 weeks after stopping therapy, HBV replication rebounded but no liver damage was detectable. There were no changes in cell frequencies at viral rebound. ScRNA-seq revealed upregulation of IFN stimulated genes (ISGs) and pro-inflammatory cytokine MIF at viral rebound in patients that go on to develop hepatic flares 6 – 18 w after stopping therapy. The type I IFN signature was only detectable within the liver and neither IFN-α/β or ISG induction could be detected in the peripheral blood. In vitro experiments confirmed the type I IFN-dependent ISG profile whereas MIF was induced primarily by IL-12. MIF exposure further amplified inflammatory cytokine production by myeloid cells. Our data show that innate immune activation is detectable in the liver before clinically significant liver damage is evident. The combination of type I IFN and enhanced cytokine production upon MIF exposure represent the earliest immunological triggers of lymphocyte bystander activation observed in hepatic flares associated with chronic HBV infection.
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Project description:development of prognostic biomarkers for HBV-related acute-on-chronic liver failure
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Project description:Neutrophil Gene expression in Acute-on-chronic liver failure (ACLF), Chronic liver disease (CLD) and Healthy Controls_AIIMSND_Aug2020
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Project description:Background and aims: We aimed to study the pathogenesis of AH in an animal model of acute-on-chronic alcoholic liver disease which combines chronic hepatic fibrosis with intragastric alcohol administration. Methods: Adult male C57BL6/J mice were treated with CCl4 (0.2 ml/kg, 2×weekly by intraperitoneal injections for 6 weeks) to induce chronic liver fibrosis. Then, ethyl alcohol (EtOH) (up to 25 g/kg/day, for 3 weeks) was administered continuously to mice via a gastric feeding tube, with or without one-half dose of CCl4. Liver and serum markers were evaluated to characterize acute-on-chronic-alcoholic liver disease in our model. Results: CCl4 or EtOH treatment alone induced liver fibrosis or steatohepatitis, respectively, findings that were consistent with expected pathology. Combined treatment with CCl4 and EtOH resulted in a marked exacerbation of liver injury, as evident by the development of hepatic inflammation, marked steatosis, and pericellular fibrosis, and by increased serum transaminase levels, compared to mice treated with either treatment alone. Liver transcriptomic changes specific to combined treatment group demonstrated close concordance with pathways perturbed in human severe cases of AH. In addition to gene expression changes, E. coli and Candida species were also significantly more abundant in livers of mice co-treated with CCl4 and EtOH. Conclusions: Mice treated with CCl4 and EtOH displayed several key characteristics of human AH, including pericellular fibrosis, increased hepatic bacterial load, and dysregulation of the same molecular pathways. This model may be useful for developing therapeutics for AH.
2018-09-05 | GSE119470 | GEO
Project description:Acute liver injury is a critical life-threatening event. Common causes are infections, intoxication, and ischemic conditions. The cytokine Interleukin 22 (IL-22) has been implicated in this process. However, the role of IL-22 during acute liver damage is controversial, since both protective and pathogenic properties have been reported. IL-22 binding protein (IL-22BP, IL-22Ra2), a soluble endogenous inhibitor of IL-22, is able to regulate IL-22 activity, and thus might explain some of the controversial findings. Since the role of IL-22BP in liver injury is unknown, we used Il22bp deficient mice and mouse models for acute liver damage to address this point. We found that Il22bp deficient mice were more susceptible to ischemia- and acetaminophen- induced liver damage. Deficiency of Il22bp caused increased hepatic damage and delayed liver regeneration. Using an unbiased approach, we found that IL-22, if uncontrolled in Il22bp deficient mice, induced Cxcl10 expression by hepatocytes, thereby recruiting inflammatory CD11b+Ly6C+ monocytes into the liver upon liver damage. Accordingly, neutralization of Cxcl10 reversed the increased disease susceptibility of Il22bp deficient mice. In conclusion, our data suggest dual functions of IL-22 in acute liver damage, and highlight the need to control IL-22 activity via IL-22BP.
2017-12-22 | GSE93034 | GEO