thromboxane-a2 and montelukast

Microbial infections are a relevant problem for patients with liver cirrhosis. Different types of bacteria are responsible for different kinds of infections: Escherichia coli and Klebsiella pneumoniae are frequently observed in spontaneous bacterial peritonitis or urinary tract infections, and Streptococcus pneumoniae and Mycoplasma pneumoniae in pulmonary infections. Mortality is up to 4-fold higher in infected patients with liver cirrhosis than in patients without infections. Key Messages: Infections in patients with liver cirrhosis are due to three major reasons: bacterial translocation, immune deficiency and an increased incidence of systemic infections. Nonparenchymal liver cells like Kupffer cells, sinusoidal endothelial cells and hepatic stellate cells are the first liver cells to come into contact with microbial products when systemic infection or bacterial translocation occurs. Kupffer cell (KC) activation by Toll-like receptor (TLR) agonists and endothelial sinusoidal dysfunction have been shown to be important mechanisms increasing portal pressure following intraperitoneal lipopolysaccharide pretreatment in cirrhotic rat livers. Reduced intrahepatic vasodilation and increased intrahepatic vasoconstriction are the relevant pathophysiological pathways. Thromboxane A2 and leukotriene (LT) C4/D4 have been identified as important vasoconstrictors. Accordingly, treatment with montelukast to inhibit the cysteinyl-LT1 receptor reduced portal pressure in cirrhotic rat livers. Clinical studies have demonstrated that activation of KCs, estimated by the amount of soluble CD163 in the blood, correlates with the risk for variceal bleeding. Additionally, intestinal decontamination with rifaximin in patients with alcohol-associated liver cirrhosis reduced the portal pressure and the risk for variceal bleeding.. TLR activation of nonparenchymal liver cells by pathogens results in portal hypertension. This might explain the pathophysiologic correlation between microbial infections and portal hypertension in patients with liver cirrhosis. These findings are the basis for both better risk stratifying and new treatment options, such as specific inhibition of TLR for patients with liver cirrhosis and portal hypertension.

Topics: Acetates; Animals; Anti-Infective Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Bacterial Translocation; Cyclopropanes; Endothelial Cells; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Gram-Negative Bacterial Infections; Hepatic Stellate Cells; Humans; Hypertension, Portal; Kupffer Cells; Leukotriene Antagonists; Leukotrienes; Liver; Liver Cirrhosis; Portal Pressure; Quinolines; Rats; Receptors, Cell Surface; Rifamycins; Rifaximin; Sulfides; Thromboxane A2; Vasoconstriction

The mechanisms underlying intrahepatic vasoconstriction are not fully elucidated. Here we investigated the Kupffer cell (KC)-dependent increase in portal pressure by way of actions of vasoconstrictive cysteinyl leukotrienes (Cys-LTs). Liver cirrhosis was induced in rats by bile duct ligation (BDL for 4 weeks; controls: sham-operation) and thioacetamide application (18 weeks). Infusion of leukotriene (LT) C(4) or LTD(4) in isolated perfused livers (20 nM, BDL and sham) demonstrated that LTC(4) is a more relevant vasoconstrictor. In BDL animals the Cys-LT(1) receptor inhibitor montelukast (1 microM) reduced the maximal portal perfusion pressure following LTC(4) or LTD(4) infusion. The infusion of LTC(4) or D(4) in vivo (15 microg/kg b.w.) confirmed LTC(4) as the more relevant vasoconstrictor. Activation of KCs with zymosan (150 microg/mL) in isolated perfused BDL livers increased the portal perfusion pressure markedly, which was attenuated by LT receptor blockade (Ly171883, 20 microM). Cys-LTs in the effluent perfusate increased with KC activation but less with additional blockade of KCs with gadolinium chloride (10 mg/kg body weight, 48 and 24 hours pretreatment). KCs were isolated from normal rat livers and activated with zymosan or lipopolysaccharide at different timepoints. This resulted in an increase in Cys-LT production that was not influenced by preincubation with montelukast (1 microM). Infusion of LTC(4) (20 nM) and the thromboxane analog U46619 (0.1 microM) further enhanced portal pressure, indicating additive effects. Treatment with montelukast for 10 days resulted in an impressive reduction in the basal portal pressure and an attenuation of the KC-dependent increase in portal pressure.. Activation of isolated KCs produced Cys-LTs. Infusion of Cys-LTs increased portal pressure and, vice versa, treatment with montelukast reduced portal pressure in rat liver cirrhosis. Therefore, montelukast may be of therapeutic benefit for patients with portal hypertension.

Topics: Acetates; Animals; Cyclopropanes; Hypertension, Portal; Kupffer Cells; Leukotriene Antagonists; Leukotrienes; Ligation; Liver; Liver Cirrhosis; Male; Quinolines; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Sulfides; Thioacetamide; Thromboxane A2