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Knockout of alpha-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice
- Source :
- Laboratory investigation; a journal of technical methods and pathology. 87(9)
- Publication Year :
- 2007
-
Abstract
- The role of sensory innervation in the regulation of liver physiology and the pathogenesis of cholestatic liver disease are undefined. Biliary proliferation has been shown to be coordinately controlled by parasympathetic and sympathetic innervation of the liver. The aim of our study was to address the role of the sensory neuropeptide calcitonin gene-related peptide (alpha-CGRP) in the regulation of cholangiocyte proliferation during cholestasis induced by extrahepatic bile duct obstruction (BDL). Our study utilized a knockout (KO) mouse model, which lacks the sensory neuropeptide alpha-CGRP. Wild-type (WT) and alpha-CGRP KO mice were subjected to sham surgery or BDL for 3 and 7 days. In addition, immediately after BDL, WT and KO mice were administered the CGRP receptor antagonist (CGRP(8-37)) for 3 and 7 days by osmotic minipumps. Liver sections and isolated cholangiocytes were evaluated for proliferation markers. Isolated WT BDL (3 days) cholangiocytes were stimulated with alpha- and beta-CGRP and evaluated for proliferation and cAMP-mediated signaling. Lack of alpha-CGRP inhibits cholangiocyte proliferation induced by BDL at both 3 and 7 days. BDL-induced cholangiocyte proliferation in WT mice was associated with increases of circulating alpha-CGRP levels. In vitro, alpha- and beta-CGRP stimulated proliferation in purified BDL cholangiocytes, induced elevation of cAMP levels, and stimulated the activation of cAMP-dependent protein kinase A and cAMP response element binding protein DNA binding. In conclusion, sensory innervation of the liver and biliary expression of alpha-CGRP play an important role in the regulation of cholangiocyte proliferation during cholestasis.
- Subjects :
- Male
medicine.medical_specialty
Cholangitis
Calcitonin Gene-Related Peptide
Cholangiocyte proliferation
Neuropeptide
Calcitonin gene-related peptide
Biology
Cholangiocyte
Pathology and Forensic Medicine
Mice
Cholestasis
Internal medicine
medicine
Animals
Protein kinase A
Biliary Tract
Molecular Biology
Cell Proliferation
Mice, Knockout
Epithelial Cells
Cell Biology
Cholestasis, Extrahepatic
medicine.disease
Disease Models, Animal
Endocrinology
Bile Ducts, Intrahepatic
Biliary tract
Calcitonin
Subjects
Details
- ISSN :
- 00236837
- Volume :
- 87
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Laboratory investigation; a journal of technical methods and pathology
- Accession number :
- edsair.doi.dedup.....cf6e2b18ff343f1eb112dded5dc55055