Increased pulmonary vascular permeability in rats with biliary cirrhosis: role of thromboxane A2.
Rats with liver cirrhosis exhibit arterial hypoxemia and loss of hypoxic pulmonary vasoconstriction similar to some patients with end-stage liver disease. We hypothesized that the pulmonary circulatory dysfunction in cirrhosis results from vascular endothelial cell injury and interstitial lung edema. To investigate this hypothesis, we compared the extravascular lung albumin leak, lung ultrastructural changes, and tissue eicosanoid levels in control and cirrhotic rats. In comparison to sham-operated controls, rats with biliary cirrhosis, 6 wk after ligation of the common bile duct, had increased lung albumin leak index (1.46 +/- 0.12 vs. 0.80 +/- 0.04, P < 0.001) and bloodless lung wet-to-dry weight ratio (4.94 +/- 0.05 vs. 4.78 +/- 0.03, P < 0.05). Electron-microscopic sections of lungs from cirrhotic rats demonstrated infiltration with intravascular macrophage-like cells, endothelial cell injury, and interstitial edema. In addition, lung tissue thromboxane B2 was significantly increased in cirrhotic rats, and pretreatment with a thromboxane synthase inhibitor, dazoxiben, reduced lung thromboxane B2 level and attenuated extravascular lung albumin leak (control 1.03 +/- 0.07, cirrhotic 2.29 +/- 0.06, cirrhotic plus dazoxiben, 1.57 +/- 0.17). In contrast, WEB 2086, a platelet-activating factor antagonist, had no effect on lung albumin leak. We conclude that pulmonary vascular permeability is increased in rats with biliary cirrhosis and that thromboxane A2 contributes to the pulmonary circulatory abnormalities in cirrhosis.
Chang
S W
SW
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Ohara
N
N
D000418:Albumins / Q000493:pharmacokinetics; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D015777:Eicosanoids / Q000032:analysis / Q000493:pharmacokinetics; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D008854:Microscopy, Electron; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013928:Thromboxane A2 / Q000502:physiology*; D013929:Thromboxane B2 / Q000032:analysis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D000418:Albumins; D015777:Eicosanoids; D007093:Imidazoles; C029166:dazoxiben; D013929:Thromboxane B2; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase