Cholangiopathies (Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC)) are characterized by the proliferation/loss of cholangiocytes, which are the cells that line the biliary epithelium. During cholestasis, biliary hyperplasia/damage is regulated by both autocrine/paracrine mechanisms. For example, during hyperplastic cholangiocyte proliferation bile duct mass increases and proliferating cholangiocytes release numerous factors like histamine presumably to sustain the increased bile duct mass. In ductopenic states, bile duct mass decreases and cholangiocytes are damaged and unable to maintain biliary homeostasis. We have shown that: (i) cholangiocytes express histamine receptors (HRs) and histidine decarboxylase (HDC), the key enzyme regulating histamine synthesis; (ii) cholangiocytes release histamine; and (iii) inhibition of biliry HDC decreases both hyperplastic and neoplastic cholangiocyte growth and vascular endothelial growth factor (VEGF) by autocrine pathways. Besides the autocrine regulation of cholangiocyte proliferation/loss, paracrine regulation of biliary function by neighboring hepatic cells must be considered. It has been demonstrated in patients with PBC and PSC that histamine plasma levels are higher and that there are increased numbers of hepatic mast cells in the proximity of bile ducts. When activated, hepatic mast cells release numerous factors like histamine into the microenvironment, which we propose influence cholangiocyte proliferative/apoptotic responses in cholangiopathies. In our proposal, we present preliminary data supporting the hypothesis that mast cells infiltrate the liver following damage via c-kit/SCF interaction and that mast cells alte the proliferative response of small and large cholangiocytes in models of liver damage or repair by interaction with H1 and H2 HRs and specific microRNAs. Our proposed studies are innovative and will likely provide important, clinically relevant data to add to the understanding f the regulation of biliary disorders and also offer insight into novel treatment strategies.

Public Health Relevance

Cholangiopathies are characterized by the proliferation or damage of cholangiocytes. Hepatic mast cell number and histamine levels increase during liver damage and may influence cholangiocyte proliferation. Patient treatments are limited and there is a need for the development of novel treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK108959-04
Application #
9416996
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
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Francis, Heather; Kennedy, Lindsey; Alpini, Gianfranco (2017) Dual ablation of ?- and ?-catenin: Critical regulators of junctions and their functions. Hepatology :
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Wan, Ying; Meng, Fanyin; Wu, Nan et al. (2017) Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells. Hepatology 66:528-541

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