TY - JOUR
T1 - Leukotriene b 4/leukotriene b 4 receptor pathway is involved in hepatic microcirculatory dysfunction elicited by endotoxin
AU - Ito, Sohei
AU - Ito, Yoshiya
AU - Katagiri, Hiroyuki
AU - Suzuki, Tatsunori
AU - Hoka, Sumio
AU - Yokomizo, Takehiko
AU - Shimizu, Takao
AU - Majima, Masataka
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
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U2 - 10.1097/SHK.0b013e31815d06a1
DO - 10.1097/SHK.0b013e31815d06a1
M3 - Article
C2 - 18004232
AN - SCOPUS:51549093018
VL - 30
SP - 87
EP - 91
JO - Shock
JF - Shock
SN - 1073-2322
IS - 1
ER -