thromboxane-b2 and Liver-Cirrhosis--Biliary

Recent studies have shown that the activated endocannabinoid system participates in the increase in IHR (intrahepatic resistance) in cirrhosis. The increased hepatic production of vasoconstrictive eicosanoids is involved in the effect of endocannabinoids on the hepatic microcirculation in cirrhosis; however, the mechanisms of these effects are still unknown. The aim of the present study was to investigate the effects of chronic CB(1) (cannabinoid 1) receptor blockade in the hepatic microcirculation of CBL (common bile-duct-ligated) cirrhotic rats. After 1 week of treatment with AM251, a specific CB(1) receptor antagonist, IHR, SMA (superior mesenteric artery) blood flow and hepatic production of eicosanoids [TXB(2) (thromboxane B(2)), 6-keto PGF(1alpha) (prostaglandin F(1alpha)) and Cys-LTs (cysteinyl leukotrienes)] were measured. Additionally, the protein levels of hepatic COX (cyclo-oxygenase) isoforms, 5-LOX (5-lipoxygenase), CB(1) receptor, TGF-beta(1) (transforming growth factor beta(1)), cPLA(2) [cytosolic PLA(2) (phospholipase A(2))], sPLA(2) (secreted PLA(2)) and collagen deposition were also measured. In AM251-treated cirrhotic rats, a decrease in portal venous pressure was associated with the decrease in IHR and SMA blood flow. Additionally, the protein levels of hepatic CB(1) receptor, TGF-beta(1), cPLA(2) and hepatic collagen deposition, and the hepatic levels of 5-LOX and COX-2 and the corresponding production of TXB(2) and Cys-LTs in perfusates, were significantly decreased after 1 week of AM251 treatment in cirrhotic rats. Furthermore, acute infusion of AM251 resulted in a decrease in SMA blood flow and an increase in SMA resistance in CBL rats. In conclusion, the chronic effects of AM251 treatment on the intrahepatic microcirculation were, at least partly, mediated by the inhibition of hepatic TGF-beta(1) activity, which was associated with decreased hepatic collagen deposition and the activated PLA(2)/eicosanoid cascade in cirrhotic livers.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonate 5-Lipoxygenase; Collagen; Leukotriene D4; Liver; Liver Cirrhosis, Biliary; Male; Mesenteric Artery, Superior; Microcirculation; Phospholipases A; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Regional Blood Flow; Thromboxane B2; Transforming Growth Factor beta; Vascular Resistance

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.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Bile Ducts; Capillary Permeability; Cholestasis; Eicosanoids; Imidazoles; Kidney; Ligation; Liver Cirrhosis, Biliary; Lung; Male; Rats; Rats, Sprague-Dawley; Serum Albumin, Radio-Iodinated; Thromboxane A2; Thromboxane B2

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.

Topics: Albumins; Animals; Capillary Permeability; Eicosanoids; Imidazoles; Liver; Liver Cirrhosis, Biliary; Lung; Macrophages; Male; Microscopy, Electron; Models, Biological; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

In a study using rats, we investigated whether liver damage induced by endotoxemia in obstructive jaundice is associated with thromboxane (TX) in order to acertain whether its vasoconstrictive and platelet aggregating properties play a role in reducing liver blood flow. The rats were divided into the following 5 groups; a control group, an endotoxin (Et) group, a bile duct ligation (BDL) group, a bile duct ligation and endotoxin (BDL + Et) group and an OKY046 (Thromboxane synthetase inhibitor) treated bile duct ligation + endotoxin (OKY-BDL + Et) group. The blood TXB2 levels in the Et, BDL and BDL + Et groups were higher than those in the control group. The liver TXB2 levels in the Et and BDL + Et groups were also higher than those in the control group. Liver phospholipids and liver blood flow decreased in the BDL + Et group, whereas in the OKY-BDL + Et group they returned close to the control group levels by decreasing the TXB2 levels in both the liver and blood to normal. These results suggest that the high level of TX in the blood and liver tissue may further aggrevate the liver during endotoxemia in obstructive jaundice by inhibiting liver blood flow.

Topics: Animals; Cholestasis, Extrahepatic; Escherichia coli Infections; Liver; Liver Circulation; Liver Cirrhosis, Biliary; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2

In a previous study we observed that after in vitro treatment with indomethacin, lymphocyte response to phytohaemagglutinin (PHA) in primary biliary cirrhosis (PBC) patients was higher than that of controls. We know that indomethacin also inhibits prostanoid production, and thus in the present work we directly measured prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) production by mononuclear cells and monocytes from 12 PBC patients, 11 control subjects, and three control disease patients (alcoholic cirrhosis, AC). PHA-stimulated enriched monocytes from PBC patients produced approximately threefold more PGE2 (after 48 h of culture) than did normal and AC monocytes (P less than 0.05). TXB2 production was similar in all groups studied. We also made cultures in which PBC-purified lymphocytes proliferated better than PBC mononuclear cells (i.e. lymphocytes plus monocytes). Thus, a monocyte population producing PGE2 could be responsible, at least in part, for the hyporesponsiveness to PHA observed in PBC patients.

Topics: Humans; Indomethacin; Liver Cirrhosis, Biliary; Lymphocyte Activation; Middle Aged; Prostaglandins E; T-Lymphocytes; Thromboxane B2

Platelet function was assessed in 28 patients with primary biliary cirrhosis (PBC), of whom 10 were receiving D-penicillamine. Patients not on D-penicillamine treatment had platelet aggregation similar to that in the healthy control group; the group treated with D-penicillamine showed significantly enhanced platelet aggregation in response to threshold doses of adrenaline and collagen but not ADP. Median thromboxane B2 production was also higher in D-penicillamine treated patients than in controls or untreated patients; this difference did not reach statistical significance. The addition of D-penicillamine in vitro to platelet rich plasma from normal subjects was shown to enhance adrenaline- and collagen-induced platelet aggregation. Abnormalities of platelet function in PBC patients did not correlate with serum cholesterol concentration or with liver function tests but were related to the stage of disease. The present study emphasises the need to consider the aetiology, disease stage and type of treatment when assessing platelet function and prostanoid release in liver disease.

Topics: Aged; Cholesterol; Female; Humans; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Penicillamine; Platelet Aggregation; Platelet Count; Thromboxane A2; Thromboxane B2