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Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice.

ABSTRACT: In bile duct-ligated (BDL) rats, cholangiocyte proliferation is regulated by neuroendocrine factors such as ?-calcitonin gene-related peptide (?-CGRP). There is no evidence that the sensory neuropeptide substance P (SP) regulates cholangiocyte hyperplasia. Wild-type (WT, (+/+)) and NK-1 receptor (NK-1R) knockout (NK-1R(-/-)) mice underwent sham or BDL for 1 wk. Then we evaluated 1) NK-1R expression, transaminases, and bilirubin serum levels; 2) necrosis, hepatocyte apoptosis and steatosis, and the number of cholangiocytes positive by CK-19 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling in liver sections; 3) mRNA expression for collagen 1? and ?-smooth muscle (?-SMA) actin in total liver samples; and 4) PCNA expression and PKA phosphorylation in cholangiocytes. In cholangiocyte lines, we determined the effects of SP on cAMP and D-myo-inositol 1,4,5-trisphosphate levels, proliferation, and PKA phosphorylation. Cholangiocytes express NK-1R with expression being upregulated following BDL. In normal NK-1R(-/-) mice, there was higher hepatocyte apoptosis and scattered hepatocyte steatosis compared with controls. In NK-1R (-)/(-) BDL mice, there was a decrease in serum transaminases and bilirubin levels and the number of CK-19-positive cholangiocytes and enhanced biliary apoptosis compared with controls. In total liver samples, the expression of collagen 1? and ?-SMA increased in BDL compared with normal mice and decreased in BDL NK-1R(-/-) compared with BDL mice. In cholangiocytes from BDL NK-1R (-)/(-) mice there was decreased PCNA expression and PKA phosphorylation. In vitro, SP increased cAMP levels, proliferation, and PKA phosphorylation of cholangiocytes. Targeting of NK-1R may be important in the inhibition of biliary hyperplasia in cholangiopathies.

SUBMITTER: Glaser S

PROVIDER: S-EPMC3154601 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice.

Glaser Shannon S Gaudio Eugenio E Renzi Anastasia A Mancinelli Romina R Ueno Yoshiyuki Y Venter Julie J White Mellanie M Kopriva Shelley S Chiasson Valorie V DeMorrow Sharon S Francis Heather H Meng Fanyin F Marzioni Marco M Franchitto Antonio A Alvaro Domenico D Supowit Scott S DiPette Donald J DJ Onori Paolo P Alpini Gianfranco G

American journal of physiology. Gastrointestinal and liver physiology 20110519 2

In bile duct-ligated (BDL) rats, cholangiocyte proliferation is regulated by neuroendocrine factors such as α-calcitonin gene-related peptide (α-CGRP). There is no evidence that the sensory neuropeptide substance P (SP) regulates cholangiocyte hyperplasia. Wild-type (WT, (+/+)) and NK-1 receptor (NK-1R) knockout (NK-1R(-/-)) mice underwent sham or BDL for 1 wk. Then we evaluated 1) NK-1R expression, transaminases, and bilirubin serum levels; 2) necrosis, hepatocyte apoptosis and steatosis, and t ...[more]

PMID: 21596993

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Project description:Disrupted bile secretion leads to liver damage characterized by inflammation, fibrosis, eventually cirrhosis, and hepatocellular cancer. As obstructive cholestasis often progresses insidiously, markers for the diagnosis and staging of the disease are urgently needed. To this end, we compiled a comprehensive data set of serum markers, histological parameters and transcript profiles at 8 time points of disease progression after bile duct ligation (BDL) in mice, aiming at identifying a set of parameters that could be used as robust biomarkers for transition of different disease progression phases.Statistical analysis of the more than 6,000 data points revealed distinct temporal phases of disease. Time course correlation analysis of biochemical, histochemical and mRNA transcript parameters (=factors) defined 6 clusters for different phases of disease progression. The number of CTGF-positive cells provided the most reliable overall measure for disease progression at histological level, bilirubin at biochemical level, and metalloproteinase inhibitor 1 (Timp1) at transcript level. Prominent molecular events exhibited by strong transcript peaks are found for the transcriptional regulator Nr0b2 (Shp) and 1,25-dihydroxyvitamin D(3) 24-hydroxylase (Cyp24a1) at 6 h. Based on these clusters, we constructed a decision tree of factor combinations potentially useful as markers for different time intervals of disease progression. Best prediction for onset of disease is achieved by fibronectin (Fn1), for early disease phase by Cytochrome P450 1A2 (Cyp1a2), passage to perpetuation phase by collagen1α-1 (Col1a1), and transition to the progression phase by interleukin 17-a (Il17a), with early and late progression separated by Col1a1. Notably, these predictions remained stable even for randomly chosen small sub-sets of factors selected from the clusters.Our detailed time-resolved explorative study of liver homogenates following BDL revealed a well-coordinated response, resulting in disease phase dependent parameter modulations at morphological, biochemical, metabolic and gene expression levels. Interestingly, a small set of selected parameters can be used as diagnostic markers to predict disease stages in mice with cholestatic liver disease.

Dataset Information

Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice.

Publications

Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice.

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