The hepatopulmonary syndrome (HPS) is an important vascular complication of liver disease where 15-30% of cirrhotic patients develop pulmonary microvascular dilatation causing hypoxemia. The presence of HPS 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 HPS. Current cycle shows that hepatic production and release of endothelin-1 (ET-1) and increased pulmonary expression of the endothelin B (ETB) receptor are critical early events that trigger HPS through eNOS derived NO production. Pulmonary 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. Increased pulmonary ETB receptor levels correlate 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 contributes 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 recruit and activate 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. Our hypothesis is that shear stress/cytokine induced pulmonary vascular endothelial ETB receptor overexpression mediates ET-1 effects in the endothelium and macrophages in experimental HPS. We will 1) define the cellular mechanisms and consequences of pulmonary vascular endothelial ETB receptor overexpression in cirrhosis and portal hypertension, 2) test if 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.

Public Health Relevance

HPS is a common clinical problem that adversely influences survival in patients with cirrhosis. The long-term goal of our studies 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 disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056804-13
Application #
8294735
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Sherker, Averell H
Project Start
1999-12-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
13
Fiscal Year
2012
Total Cost
$308,138
Indirect Cost
$102,713
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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