Roles of Thromboxane in Lipopolysaccharide-Induced Hepatic Microcirculatory Dysfunction in Mice

Abstract

Although thromboxanes (TXs) have been suggested to promote inflammation in the liver, little is known about the role of TXA(2) in leukocyte-endothelial interaction during endotoxemia. We observed using in vivo fluorescence microscopy that lipopolysaccharide (LPS) caused significant accumulation of leukocytes adhering to the hepatic microvessels and non-perfused sinusoids. Levels of serum alanine transaminase (ALT) and tumor necrosis factor alpha (TNFalpha) also increased. Lipopolysaccharide raised TXB2 level in the perfusate from isolated perfused liver. A TXA(2) synthase inhibitor, OKY-046, and a TXA(2) receptor antagonist, S-1452, reduced LPS-induced hepatic microcirculatory dysfunction by inhibiting TNFalpha production. OKY-046 suppressed expression of intercellular adhesion molecule (ICAM)-1 in LPS-treated liver. In thromboxane prostanoid receptor-knockout mice, hepatic responses to LPS were minimized in comparison with those in their wild-type counterparts. These results suggest that TXA(2) is involved in LPS-induced hepatic microcirculatory dysfunction partly through the release of TNFalpha, and that endogenous TXA(2) could be responsible for the microcirculatory dysfunction during endotoxemia.