(Chest. 2005;128:580S-581S.)
© 2005
American College of Chest Physicians
Endothelin-B Receptor Overexpression Prevents Hypoxic Pulmonary Hypertension in Cirrhotic Rats*
Masatoshi Imamura;
Andrea M. Vitello;
Jennifer N. Limbird;
D. Dunbar Ivy;
Michael B. Fallon and
Ethan P. Carter
* From Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver, CO; and University of Alabama at Birmingham, Birmingham, AL.
Correspondence to: Masatoshi Imamura, Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver, CO; e-mail: masatoshi.imamura{at}uchsc.edu
Pulmonary vascular complications during liver cirrhosis can be frequent and severe. A prominent feature of hepatopulmonary syndrome is blunted hypoxic pulmonary vasoconstriction (HPV), illustrating that the acute response to hypoxia is impaired during cirrhosis. The pulmonary response to chronic hypoxia (CH) is unknown. Our purpose was to characterize the pulmonary adaptations to CH in rats with advanced biliary cirrhosis. To investigate this interaction, we induced liver cirrhosis in the rats using common bile duct ligation (CBDL) and exposed them to CH or maintained them in Denver (Den) for 3 weeks. Histologic, biochemical, and hemodynamic responses were evaluated. The response to acute hypoxia, which was assessed by measuring HPV in isolated lungs, was blunted in both the CBDL-Den and CBDL-CH groups. The response to CH was strikingly different. The CBDL-CH rats did not develop pulmonary hypertension compared to the sham-Den rats (mean [± SD] pulmonary artery pressure: sham-Den rats, 19.0 ± 1.2 mm Hg; sham-CH rats, 45.1 ± 2.0 mm Hg; CBDL-CH rats, 23.9 ± 2.1 mm Hg) and showed no evidence of pulmonary arteriole remodeling (Fig 1
) or right ventricular hypertrophy (sham-Den rats, 0.31 ± 0.02 mm Hg; sham-CH rats, 0.59 ± 0.04 mm Hg; CBDL-CH rats, 0.33 ± 0.02 mm Hg).
Persistent pulmonary vasodilation during cirrhosis was recently shown to be mediated by elevated circulating endothelin (ET)-1 levels combined with overexpression of the ETb receptor on endothelial cells. ET-1 and lung ETb expression were significantly elevated in the CBDL-CH rats, while ETa receptor expression was decreased (Fig 2
). Additionally, CBDL-Den rats that were deficient of lung ETb receptors (spotted lethal rats) had normal HPV compared to control Sprague-Dawley CBDL-Den rats (Fig 3
). Taken together, these data demonstrate that ETb receptor overexpression not only mediates pulmonary vasodilation during hepatopulmonary syndrome but may also be protective against the development of hypoxic pulmonary hypertension.
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Figure 2. Top, A: pulmonary Western blots (upper panel) and corresponding densitometry (lower panel) for ETa receptor (white and gray columns) and ETb receptor (crosshatch and black columns). Bottom, B: pulmonary ET-1 levels measured by enzyme-linked immunosorbent assay (n = 3 to 4 for all groups).
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Figure 3. HPV in Sprague-Dawley (SD) rats and spotted lethal (sl) rats following CBDL. The tracings of HPV in isolated lungs from Sham and CBDL rats. All data are from rats housed at the altitude of Denver.
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Footnotes
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Abbreviations: CBDL = common bile duct ligation; CH = chronic hypoxia; Denver = Den; ET = endothelin; HPV = hypoxic pulmonary vasoconstriction
