Leukotriene b ₄/leukotriene b ₄ receptor pathway is involved in hepatic microcirculatory dysfunction elicited by endotoxin

Leukotrienes (LTs), metabolites of arachidonic acid through 5-lipoxygenase (5-LOX), have been known to play a role in leukocyte recruitment. However, the contribution of LTB ₄ to liver microcirculatory dysfunction during endotoxemia remains unknown. LTB ₄ receptor (BLT1) has been identified as a high-affinity receptor specific for LTB ₄. The present study was conducted to examine the roles of LTB ₄ and BLT1 in hepatic microcirculatory dysfunction elicited by LPS in mice. The number of leukocytes adhering to the endothelial cells of the hepatic microvessels and perfused sinusoids was determined 4 h after the administration of LPS (0.3 mg/kg, i.v.) to male C57B16 mice by in vivo microscopy. A 5-LOX synthase inhibitor, AA-861 (10 or 100 mg/kg, s.c.), was administered 30 min before LPS injection. BLT1 knockout mice were used to investigate whether LPS-induced hepatic microcirculatory dysfunction is mediated by BLT1 signaling. The expression of 5-LOX, intercellular adhesion molecule (ICAM) 1, and TNF-α in the liver was measured by real-time reverse-transcriptase-polymerase chain reaction. The administration of LPS caused significant accumulation of leukocyte adhesion to the hepatic microvessels and reduced sinusoidal perfusion when compared with saline-treated mice. The hepatic microcirculatory dysfunction elicited by LPS was minimized in mice pretreated with AA-861 or in BLT1 knockout mice. This was associated with the suppression of hepatic expression of 5-LOX, ICAM-1, and TNF-α. These findings suggest that the LTB ₄/BLT1 pathway mediates hepatic microcirculatory dysfunction by enhanced expression of ICAM-1 and TNF-α in a murine model of endotoxemia.