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

Summary

Although thromboxanes (TXs) have been suggested to promote inflammation in the liver, little is known about the role of TXA₂ 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 α (TNFα) also increased. Lipopolysaccharide raised TXB₂ level in the perfusate from isolated perfused liver. A TXA₂ synthase inhibitor, OKY-046, and a TXA₂ receptor antagonist, S-1452, reduced LPS-induced hepatic microcirculatory dysfunction by inhibiting TNFα 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 TXA₂ is involved in LPS-induced hepatic microcirculatory dysfunction partly through the release of TNFα, and that endogenous TXA₂ could be responsible for the microcirculatory dysfunction during endotoxemia.