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Knockout of the Neurokinin-1 Receptor Reduces Cholangiocyte Proliferation in Bile Duct Ligated Mice.

著者 Glaser S , Gaudio E , Renzi A , Mancinelli R , Ueno Y , Venter J , White M , Kopriva S , Chiasson VL , Demorrow S , Francis H , Meng F , Marzioni M , Franchitto A , Alvaro D , Supowit SC , Dipette DJ , Onori P , Alpini G この記事をPubMed上で見るPubMedで表示
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1Scott & White Hospital, Texas A&M HSC College of Medicine.

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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) knock-out (NK-1R (-/-)) mice underwent sham or BDL for 1 week. Then, we evaluated: (i) NK-1R expression, transaminases and bilirubin serum levels; (ii) necrosis, hepatocyte apoptosis and steatosis and the number of cholangiocytes positive by CK-19 and TUNEL in liver sections; (iii) mRNA expression for collagen 1α and α-smooth muscle (α-SMA) actin in total liver samples; and (iv) PCNA expression and PKA phosphorylation in cholangiocytes. In cholangiocyte lines, we determined the effects of SP on cAMP and IP(3) levels, proliferation and PKA phosphorylation. Cholangiocytes express NK-1R with expression upregulated following BDL. In normal NK-1R ((-/-)) mice, there was higher hepatocyte apoptosis and scattered hepatocyte steatosis compared to 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 to controls. In total liver samples, the expression of collagen 1α and α-SMA increased in BDL compared to normal mice and decreased in BDL NK1-R ((-/-)) compared to 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.
PMID: 21596993 [PubMed - as supplied by publisher]
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