The hepatopulmonary syndrome (HPS) is an important vascular complication of liver disease where 15-20% of cirrhotic patients develop pulmonary microvascular dilatation leading to hypoxemia. The presence of HPS significantly increases mortality and no medical therapies are available. Experimental biliary cirrhosis induced by common bile duct ligation (CBDL) reproduces the pulmonary vascular and gas exchange abnormalities of human -IPS. Work in the current cycle has shown that production and release of endothelin-1 (ET-1) from the liver and increased expression of the endothelin B (ETB) receptor in the pulmonary vascular endothelium are critical early events that trigger HPS through eNOS derived NO production. Pulmonary endothelial ETB receptor expression is also increased in prehepatic portal hypertension but hepatic ET-1 production does not rise and HPS does not develop unless ET-1 is infused. The increase in pulmonary ETB receptor levels correlates with the development of a hyperdynamic circulation reflecting increased vascular shear stress, a known modulator of ETB receptor expression. As ET-1 and ETB receptor alterations occur after CBDL, macrophages also accumulate in the pulmonary vasculature and we have found that they contribute to the progression of HPS at later time points, by producing heme oxygenase-1 derived carbon monoxide. Whether ET-1 and ETB receptor mediated effects also play a role in the recruitment and activation of macrophages in the lung is unknown. Preliminary studies support that shear stress and ET-1 contribute to pulmonary ETB receptor overexpression in experimental HPS and reveal that selective ETB receptor inhibition may decrease pulmonary microvascular eNOS, inhibit accumulation of pulmonary intravascular macrophage and improve HPS. Based on these findings, our hypothesis is that shear stress/cytokine induced pulmonary vascular endothelial ETB receptor overexpression mediates ET-1 effects in the endothelium and macrophages during the onset and progression of experimental HPS. To test this hypothesis we will 1) define the cellular mechanisms and consequences of pulmonary vascular endothelial ETB receptor overexpression in cirrhosis and portal hypertension, 2) test the hypothesis that ET-1 and ETB receptor mediated effects contribute to adhesion and activation of monocytes/macrophages in the pulmonary vascular endothelium and 3) assess the role of ETB receptor alterations in the pathogenesis of experimental HPS in vivo. Our long-term goal is to use an understanding of vascular dysfunction in HPS to develop medical therapies and as a paradigm for understanding the pathogenesis of other vascular complications of liver. ? ? ? ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Doo, Edward
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Raevens, Sarah; Fallon, Michael B (2018) Potential Clinical Targets in Hepatopulmonary Syndrome: Lessons From Experimental Models. Hepatology 68:2016-2028
Goldberg, David S; Fallon, Michael B (2013) Model for end-stage liver disease-based organ allocation: managing the exceptions to the rules. Clin Gastroenterol Hepatol 11:452-3
Fallon, Michael B; Zhang, Junlan (2013) The lung in liver disease: old problem, new concepts. Trans Am Clin Climatol Assoc 124:250-62
Tanikella, Rajasekhar; Fallon, Michael B (2013) Hepatopulmonary syndrome and liver transplantation: who, when, and where? Hepatology 57:2097-9
Rubin, Moises Ilan Nevah; Thosani, Nirav C; Tanikella, Rajasekhar et al. (2013) Endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis: testing the current guidelines. Dig Liver Dis 45:744-9
Fritz, Jason S; Fallon, Michael B; Kawut, Steven M (2013) Pulmonary vascular complications of liver disease. Am J Respir Crit Care Med 187:133-43
Mehta, Shivang S; Fallon, Michael B (2013) Muscle cramps in liver disease. Clin Gastroenterol Hepatol 11:1385-91; quiz e80
Li, Quan; Qu, Hui-Qi; Rentfro, Anne R et al. (2012) PNPLA3 polymorphisms and liver aminotransferase levels in a Mexican American population. Clin Invest Med 35:E237-45
Zhang, Junlan; Fallon, Michael B (2012) Hepatopulmonary syndrome: update on pathogenesis and clinical features. Nat Rev Gastroenterol Hepatol 9:539-49
Zhang, Junlan; Yang, Wenli; Luo, Bao et al. (2012) The role of CX?CL1/CX?CR1 in pulmonary angiogenesis and intravascular monocyte accumulation in rat experimental hepatopulmonary syndrome. J Hepatol 57:752-8

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