Cholangiocyte growth and remodeling are critical for the maintenance of biliary mass and secretory function during the pathogenesis of chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Cholangiocytes, the epithelia lining the biliary system, participate in a diverse array of cellular processes. In cholestatic livr diseases, cholangiocytes, through the products of their cellular activation, are implicated as the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. Targeting specific factors that respond to the mechanical stress resulting from tissue injury may help limit inflammation and fibrosis that occur in hepatobiliary damages and diseases such as PBC, PSC and liver fibrosis. Emerging evidence indicates that exposure to cigarette smoke may stimulate the progression of chronic liver disease towards fibrosis such as PSC, PBC, chronic hepatitis C, and non-alcoholic fatty liver disease. Although mechanical stress such as occurs with biliary distention (commonly observed in PSC) and tobacco use (accelerates fibrosis in patients with PBC) activate cholangiocytes, the cellular and molecular mechanisms responsible for this phenotype remain unclear. The ?7-nicotinic acetylcholine receptor (?7-nAChR) mediates the proliferative and fibrogenic effects of nicotine and can also be activated by mechanical stress. We propose the overall hypothesis that ?7-nAChR activation is a key and common pathway responsible for mediating the profibrogenic cholangiocyte phenotype. This postulate will be tested in three Specific Aims, which will determine whether (i) ligand-dependent activation of ?7-nAChR during mechanical stress induces a profibrogenic phenotype via enhanced expression of miR-181 and -200; (ii) activation of mechanosensitive ?7-nAChR stimulates Ca2+-dependent ACh secretion and miR-181 and -200 expression; and (iii) inhibition of ?7-nAChR attenuates the activated biliary phenotype and fibrosis in vivo in cholestatic BDL mice. Completion of proposed studies will provide a framework for understanding how mechanical stimuli trigger local and systemic responses mediate hepatobiliary fibrosis. The findings will likely lead to new therapeutic approaches for cholestatic liver diseases and a reduction of morbidity and mortality in American Veterans with liver diseases.

Public Health Relevance

The health relatedness of this grant proposal is that effective treatments are lacking for chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases cause proliferation/damage of bile ducts in the liver. Management of chronic liver diseases represents one of the major challenges for the Veterans Administration. There is a high risk and incidence of chronic cholestatic liver diseases due to alcohol and hepatitis viruses in veterans, which is one of the most common reasons for hospitalization and mortality in American Veterans. The successful completion of the studies can be expected to provide a greater understanding of cholestatic liver disease progression and to increase opportunities for the development of novel treatment paradigms for the management of chronic liver diseases.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Gastroenterology (GAST)
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Olin Teague Veterans Center
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Sato, Keisaku; Marzioni, Marco; Meng, Fanyin et al. (2018) Ductular Reaction in Liver Diseases: Pathological Mechanisms and Translational Significances. Hepatology :
Wu, Nan; McDaniel, Kelly; Zhou, Tianhao et al. (2018) Knockout of microRNA-21 attenuates alcoholic hepatitis through the VHL/NF-?B signaling pathway in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 315:G385-G398
Wu, Nan; Meng, Fanyin; Zhou, Tianhao et al. (2018) The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-?1-Mediated Biliary Senescence. Am J Pathol 188:2264-2280
Zhou, Tianhao; Wu, Nan; Meng, Fanyin et al. (2018) Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes. Lab Invest 98:1449-1464
Ehrlich, Laurent; Scrushy, Marinda; Meng, Fanyin et al. (2018) Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease. Clin Res Hepatol Gastroenterol 42:296-305
Lewis, Phillip L; Su, Jimmy; Yan, Ming et al. (2018) Complex bile duct network formation within liver decellularized extracellular matrix hydrogels. Sci Rep 8:12220
Sato, Keisaku; Meng, Fanyin; Giang, Thao et al. (2018) Mechanisms of cholangiocyte responses to injury. Biochim Biophys Acta Mol Basis Dis 1864:1262-1269
Cai, Yuli; Li, Honggui; Liu, Mengyang et al. (2018) Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity. Hepatology 68:48-61
Raggi, Chiara; Correnti, Margherita; Sica, Antonio et al. (2017) Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages. J Hepatol 66:102-115
McMillin, Matthew; DeMorrow, Sharon; Glaser, Shannon et al. (2017) Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats. Am J Physiol Gastrointest Liver Physiol 313:G410-G418

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