Tissue eicosanoids and vascular permeability in rats with chronic biliary obstruction

Abstract

Advanced cirrhosis is known to be associated with extrahepatic organ dysfunction, but the mechanism for this cirrhosis complication is largely unknown. We measured tissue albumin leakage in rats with biliary cirrhosis or acute cholestasis and tested the hypothesis that arachidonic acid metabolites contribute to the vascular permeability change. Six weeks after bile duct ligation, rats with biliary cirrhosis exhibited increased extravascular leakage of 125I-albumin in lung (p < 0.001) and kidney (p < 0.01) but not in heart or brain. In contrast, in cholestatic rats 10 days after bile duct ligation, only the kidney albumin leak was significantly increased (p < 0.01). Tissue thromboxane B2 levels, measured with an enzyme immunoassay, were increased in lung, kidney and liver of cirrhotic and cholestatic rats. To determine whether thromboxane A2 contributes to the vascular permeability defects in cirrhosis, we pretreated cirrhotic rats with the thromboxane synthase inhibitor dazoxiben (10 mg/kg intraperitoneally every 8 hr) for 20 hr before assessment of vascular permeability. Dazoxiben blocked the increase in thromboxane B2 level in lung but not in kidney and lowered the lung but not the kidney albumin leak index. In cholestatic rats given a higher dose of dazoxiben (40 mg/kg intraperitoneally every 8 hr) for 20 hr, the kidney thromboxane B2 level but not albumin leak was significantly lowered. We conclude that chronic biliary obstruction in rats leads to increased vascular permeability in selected extrahepatic organs and that thromboxane A2 contributes to the vascular permeability increase in the lung. Whether thromboxane A2 plays a role in renal albumin leakage will require further study.

Liver cirrhosis induces renal and liver phospholipase A2 activity in rats.

“…Eventually liver failure causes extrahepatic organ dysfuntion such as hepatorenal or hepatopulmonary syndrome (8)(9)(10). These changes resemble those seen in patients or animals with septicemia (11)(12)(13)(14).…”

“…Changes in arachidonic acid derived prostaglandins have been linked to hemodynamic alterations in cirrhotic disease states (11,(15)(16)(17)(18)(19). Renal perfusion and glomerular filtration are only maintained through the vasodilatory effect of prostaglandins.…”

Stimulation of G Protein–Coupled Bile Acid Receptor Enhances Vascular Endothelial Barrier Function via Activation of Protein Kinase A and Rac1

“…Treatment with a relatively high concentration (1.5-2 mM) of bile acid, deoxycholic acid or taurochenodeoxycholic acid, increased cerebrovascular permeability by disrupting plasma membrane and intercellular junction of endothelial cells in the blood-brain barrier (Greenwood et al, 1991). A well-established cirrhosis model, common bile duct-ligated rats, displayed vascular hyperpermeability, which was accompanied with high serum bile acids Ohara et al, 1993). Although the detailed mechanisms are unclarified, these barrier-disrupting effects of bile acids might not be due to GPBAR-mediated signaling but possibly are due to the physicochemical property of bile acids as detergents.…”

LPS exacerbates endothelin-1 induced activation of cytosolic phospholipase A2 and thromboxane A2 production from Kupffer cells of the prefibrotic rat liver

“…In addition, we and others have shown increased hepatic productions of cyclooxygenase (COX)-derived prostanoids in the carbon tetrachloride and Bile Duct Ligation (BDL) animal models of cirrhosis as well as in patients with cirrhosis [13][14][15][16][17]. Thromboxane A 2 is a potent COX-derived vasoconstrictor in the portal circulation [18,19], which we have found released significantly during the early stage of BDL-induced fibrosis [17].…”