Endothelial dysfunction underlies the vascular abnormalities of chronic liver disease and is characterized by changes in the levels and activity of endothelial nitric oxide synthase. How these changes occur and why there is variability in the vascular beds involved is incompletely characterized. The hepatopulmonary syndrome is one important vascular complication of liver disease where 15-20 percent of patients with cirrhosis develop pulmonary microvascular dilatation leading to hypoxemia. No effective medical therapies are available. Experimental biliary cirrhosis reproduces the pulmonary vascular and gas exchange abnormalities of human hepatopulmonary syndrome in association with an increase in pulmonary microvascular endothelial nitric oxide levels and activity. Pre-hepatic portal hypertension alone does not cause pulmonary vascular or endothelial nitric oxide synthase alterations, implying that mediators released during hepatic injury may trigger endothelial alterations in the lung. Hepatic and plasma endothelin-1 levels rise and correlate directly with the degree of intrapulmonary vasodilatation in experimental biliary cirrhosis and preliminary studies reveal that chronic low level endothelin-1 infusion in pre-hepatic portal hypertensive animals results in selective pulmonary microvascular dilatation. Although classically recognized as a vasoconstrictor, circulating endothelin-1 stimulates endothelial cell endothelial nitric oxide synthase activity and can cause vasodilatation. Our hypothesis is that endothelin-1, released into the circulation during liver injury, preferentially activates pulmonary vascular endothelial nitric oxide synthase and triggers pulmonary microvascular dilatation. To test this hypothesis our specific aims will 1) define the effects of chronic endothelin-1 infusion on the development of intrapulmonary vasodilatation and endothelial nitric oxide synthase expression and activity in normal, pre- hepatic portal hypertensive and biliary cirrhotic animals in vivo 2) assess the effects of exogenous emdothelin-1 on endothelial nitric oxide synthase expression and activity in isolated pulmonary vascular segments and endothelial cells from normal, pre-hepatic portal hypertensive and biliary cirrhotic animals and 3) directly measure the effects of exogenous endothelin-1 on pulmonary microvascular reactivity in normal, pre-hepatic portal hypertensive and biliary cirrhotic animals. Our long-term goal is to use an understanding of endothelial dysfunction in hepatopulmonary syndrome to develop specific medical therapies and as a paradigm for understanding the pathogenesis of other vascular complications of liver disease.
| Raevens, Sarah; Fallon, Michael B (2018) Potential Clinical Targets in Hepatopulmonary Syndrome: Lessons From Experimental Models. Hepatology 68:2016-2028 |
| Mehta, Shivang S; Fallon, Michael B (2013) Muscle cramps in liver disease. Clin Gastroenterol Hepatol 11:1385-91; quiz e80 |
| 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 |
| 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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