The cellular mechanisms governing the regulation of pulmonary vascular tone are complex and incompletely understood, particularly during pathphysiological conditions. One such pathophysiological condition is hepatopulmonary syndrome. Hepatopulmonary syndrome is a clinical triad of advanced liver disease (usually cirrhosis), pulmonary gas exchange abnormalities (i.e. shunting) leading to severe systemic arterial hypoxemia, and widespread pulmonary vasodilations in the absence of intrinsic cardiopulmonary disease. This syndrome occurs in 15 - 30 percent of cirrhotic individuals and vastly complicates their treatment. Nitric oxide (NO) has been postulated to be central to the development of hepatopulmonary syndrome. An animal model of hepatopulmonary syndrome recently has been developed in rats that has proven useful for investigating to pathogenesis of hepatopulmonary syndrome. These animals have intrapulmonary shunting and hypoxemia. The mechanisms linking NO to the development of hepatopulmonary syndrome have not been defined. This proposal investigates the underlying mechanisms of hepatopulmonary syndrome using a comprehensive approach of in vivo and in vitro experimental strategies. We provide preliminary data demonstrating that in addition to elevated NO and eNOS, expression in lung of the vasocontrictor endothelin (ET-1) is decreased in cirrhotic rats. Evidence is also provided showing that vascular smooth muscle potassium channels are activated during cirrhosis. These are the first data ever, providing a mechanism for the pulmonary vasodilation and blunted hypoxic pressor response during cirrhosis. Additional data is shown demonstrating that during cirrhosis the stress response gene heme oxygenase-1 (HO-1) is significantly upregulated in lung and liver and decreased in kidney. HO-1 enzymatic activity liberates CO, a known vasodilator that can act via cGMP-dependent and -independent pathways. Therefore, it is possible that the tissue-specific regulation of the HO-1/CO axis contributes to the pulmonary vasodilation and renal vasoconstriction during cirrhosis. Finally, to investigate the role of NO in alterations to ET-1, potassium channels, and HO-1, cirrhotic rats were chronically treated with a NO inhibitor. This treatment resulted in a complete reversal of the cirrhotic associated changes to gene expression. Taken together, our data suggest that during cirrhosis, NO is central to the development of hepatopulmonary syndrome acting not only as a vasodilator but also as a regulator of gene expression of ET-1, potassium channels, and HO-1. We will test the hypotheses that: (1) chronic NO elevation during cirrhosis renders the pulmonary circulation unresponsive to hypoxia via direct vasodilatory actions and indirect modifications to gene expression; (2) factors released by the cirrhotic liver regulate pulmonary vascular tone; (3) HO-1 derived CO contributes to the pulmonary vasodilation during cirrhosis. This project will not only define the cellular basis for hepatopulmonary syndrome, but will also contribute to our understanding of how pulmonary vascular tone is controlled at the most basic level.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL064919-01A1
Application #
6400539
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Garfinkel, Susan J
Project Start
2001-08-01
Project End
2005-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$227,953
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Carter, Ethan P; Garat, Chrystelle; Imamura, Masatoshi (2004) Continual emerging roles of HO-1: protection against airway inflammation. Am J Physiol Lung Cell Mol Physiol 287:L24-5
Morio, Yoshiteru; Carter, Ethan P; Oka, Masahiko et al. (2003) EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs. Am J Physiol Heart Circ Physiol 284:H1762-70
Miyazono, Motoaki; Zhu, Daling; Nemenoff, Raphael et al. (2003) Increased epoxyeicosatrienoic acid formation in the rat kidney during liver cirrhosis. J Am Soc Nephrol 14:1766-75
Carter, Ethan P; Hartsfield, Cynthia L; Miyazono, Motoaki et al. (2002) Regulation of heme oxygenase-1 by nitric oxide during hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol 283:L346-53
Miyazono, Motoaki; Garat, Chrystelle; Morris Jr, Kenneth G et al. (2002) Decreased renal heme oxygenase-1 expression contributes to decreased renal function during cirrhosis. Am J Physiol Renal Physiol 283:F1123-31