The current pharmacologic and surgical therapies for portal hypertension a notoriously frustrating, often fatal, clinical complication of liver cirrhosis, have limited success due to the lack of clear understanding of its pathophysiology. Our work strongly indicates a major role of endothelin-1 (ET-1), a powerful vasoconstrictor, mitogen and fibrogen, in these pathologies. We observed progressive increases in hepatic ET-1 and its receptors during carbon tetrachloride (CC14)-induced cirrhosis in rats, and in cirrhotic humans. We demonstrated that a ET-1 receptor antagonist TAK-044 ameliorates portal hypertension and hepatic injury in CC14-treated rats. Further, we have shown that ET-1 stimulates the synthesis of a potent fibrogenic agent transforming growth factor-beta1, and exerts contractile and fibrogenic effects in perisinusoidal stellate cells. Stellate cells, the physiologic regulators of hepatic architecture and vascular tone, proliferate and transform into highly contractile and excessively fibrogenic myofibroblasts during liver cirrhosis. ET-1 also stimulates synthesis of a potent hepatic vasoconstrictor and systemic vasodilator platelet-activating factor (PAF) in Kupffer cells. PAF has been suggested to play a major role in hemodynamic abnormalities associated with cirrhosis. These observations indicate that interactions between ET-1, stellate cells and Kupffer cells are the major mechanism in the pathogenesis and complications of liver cirrhosis. Therefore, we propose to distinguish precise sites of changes in ET-1 and its receptors during the development of CC14-induced cirrhosis using the techniques of immunohistochemistry, in situ hybridization and cell fractionation. We will also delineate the mechanisms of (1) the elevated ET-1 levels during the development of cirrhosis; (2) the actions of ET-1 in causing structural and functional changes in stellate cells; and (3) the interactions between ET-1 and Kupffer cells with specific focus on PAF synthesis. Finally, we propose to evaluate the therapeutic potential of ET-1 receptor antagonists by administering them to rats (a) during the entire period of CC14 treatment; (b) from the time of transition between fibrosis and cirrhosis; and (c) after the development of cirrhosis to ascertain amelioration or reversal of the pathologic process. Thus, in addition to the determination of the molecular mechanisms of the role of ET-1 in liver cirrhosis, this investigation will provide valuable information for the development of appropriate therapeutic strategies for liver cirrhosis and its complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054411-05
Application #
6523725
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Doo, Edward
Project Start
1998-09-25
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
5
Fiscal Year
2002
Total Cost
$226,647
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Dangi, Anil; Huang, Chao; Tandon, Ashish et al. (2016) Endotoxin-stimulated Rat Hepatic Stellate Cells Induce Autophagy in Hepatocytes as a Survival Mechanism. J Cell Physiol 231:94-105
Gandhi, Chandrashekhar R; Chaillet, J Richard; Nalesnik, Michael A et al. (2015) Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice. Gastroenterology 148:379-391.e4
Harvey, Stephen A K; Dangi, Anil; Tandon, Ashish et al. (2013) The transcriptomic response of rat hepatic stellate cells to endotoxin: implications for hepatic inflammation and immune regulation. PLoS One 8:e82159
Sumpter, Tina L; Dangi, Anil; Matta, Benjamin M et al. (2012) Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO. J Immunol 189:3848-58
Gandhi, Chandrashekhar R (2012) Oxidative Stress and Hepatic Stellate Cells: A PARADOXICAL RELATIONSHIP. Trends Cell Mol Biol 7:1-10
Vodovotz, Yoram; Prelich, John; Lagoa, Claudio et al. (2012) Augmenter of liver regeneration (ALR) is a novel biomarker of hepatocellular stress/inflammation: in vitro, in vivo and in silico studies. Mol Med 18:1421-9
Gandhi, Chandrashekhar R; Murase, Noriko; Starzl, Thomas E (2010) Cholera toxin-sensitive GTP-binding protein-coupled activation of augmenter of liver regeneration (ALR) receptor and its function in rat kupffer cells. J Cell Physiol 222:365-73
Jameel, Noor Mohamed; Thirunavukkarasu, Chinnasamy; Murase, Noriko et al. (2010) Constitutive release of powerful antioxidant-scavenging activity by hepatic stellate cells: protection of hepatocytes from ischemia/reperfusion injury. Liver Transpl 16:1400-9
Jameel, Noor Mohamed; Thirunavukkarasu, Chinnasamy; Wu, Tong et al. (2009) p38-MAPK- and caspase-3-mediated superoxide-induced apoptosis of rat hepatic stellate cells: reversal by retinoic acid. J Cell Physiol 218:157-66
Han, Chang; Li, Guiying; Lim, Kyu et al. (2008) Transgenic expression of cyclooxygenase-2 in hepatocytes accelerates endotoxin-induced acute liver failure. J Immunol 181:8027-35

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