Dataset Information

Analysis of Pathological Activities of CCN Proteins in Fibrotic Diseases: Liver Fibrosis.

ABSTRACT: Hepatic fibrosis is a complex pathology arising from chronic injury. Pathological features are dominated by the excessive production of extracellular matrix proteins, particularly collagens which are deposited as insoluble scar material that can compromise tissue function. Fibrosis in the liver can often be assessed by staining for collagen in tissue sections and this is an approach that is widely used for grading of fibrosis in human biopsies. However, the recognition of the molecular components that drive fibrosis, including CCN proteins, and the involvement of hepatic stellate cells (HSC) as the principal collagen-producing cells in fibrosing liver, has resulted in a wide variety of molecular and cellular approaches to study the pathogenesis of fibrosis both in vivo and in vitro.

SUBMITTER: Chen L

PROVIDER: S-EPMC6032510 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Analysis of Pathological Activities of CCN Proteins in Fibrotic Diseases: Liver Fibrosis.

Chen Li L Brigstock David R DR

Methods in molecular biology (Clifton, N.J.) 20170101

Hepatic fibrosis is a complex pathology arising from chronic injury. Pathological features are dominated by the excessive production of extracellular matrix proteins, particularly collagens which are deposited as insoluble scar material that can compromise tissue function. Fibrosis in the liver can often be assessed by staining for collagen in tissue sections and this is an approach that is widely used for grading of fibrosis in human biopsies. However, the recognition of the molecular component ...[more]

PMID: 27734396

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Project description:BackgroundThe development of hepatocellular carcinoma (HCC) is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR) 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN), with HCC formation depending amongst others on interleukin (IL) 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis.MethodsABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ) for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6) as well as hepatic apoptosis (TUNEL) and proliferation (Ki67) rates.ResultsHepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN.ConclusionThis study demonstrates that liver injury upon DEN challenge depends on pre-existing fibrosis and genetic background. The generation of ABCB4-/: TLR4-/- double-deficient mice illustrates that TLR4-deficiency protects against hepatic injury in a preclinical mouse model of chronic liver disease.

Dataset Information

Analysis of Pathological Activities of CCN Proteins in Fibrotic Diseases: Liver Fibrosis.

Publications

Analysis of Pathological Activities of CCN Proteins in Fibrotic Diseases: Liver Fibrosis.

Similar Datasets

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