title: Role of thromboxane derived from COX-1 and -2 in hepatic microcirculatory dysfunction during endotoxemia in mice.
abstract: Although thromboxanes (TXs), whose synthesis is regulated by cyclooxygenase (COX), have been suggested to promote inflammation in the liver, little is known about the role of TXA(2) in leukocyte endothelial interaction during endotoxemia. The present study was conducted to investigate the role of TXA(2) as well as that of COX in lipopolysaccharide (LPS)-induced hepatic microcirculatory dysfunction in male C57Bl/6 mice. We observed during in vivo fluorescence microscopic study that 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 (TNF alpha) also increased. LPS raised the TXB(2) 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 TNF alpha production. OKY-046 suppressed the expression of an intercellular adhesion molecule (ICAM)-1 in an LPS-treated liver. In thromboxane prostanoid receptor-knockout mice, hepatic responses to LPS were minimized in comparison with those in their wild-type counterparts. In addition, a selective COX-1 inhibitor, SC-560, a selective COX-2 inhibitor, NS-398, and indomethacin significantly attenuated hepatic responses to LPS including microcirculatory dysfunction and release of ALT and TNF alpha. The effects of the COX inhibitors on hepatic responses to LPS exhibited results similar to those obtained with TXA(2) synthase inhibitor, and TXA(2) receptor antagonist. In conclusion, these results suggest that TXA(2) is involved in LPS-induced hepatic microcirculatory dysfunction partly through the release of TNF alpha, and that TXA(2) derived from COX-1 and COX-2 could be responsible for the microcirculatory dysfunction during endotoxemia.
authors.affiliation: Departments of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Ishii
authors.forename: Izumi
authors.initials: I
authors.lastname: Hayashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Shohei
authors.initials: S
authors.lastname: Yamashina
authors.forename: Takahiko
authors.initials: T
authors.lastname: Murata
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Akira
authors.initials: A
authors.lastname: Kakita
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019446:Endotoxemia / Q000378:metabolism* / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008102:Liver Circulation / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins; D008689:Methacrylates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000235:genetics; D013928:Thromboxane A2 / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008689:Methacrylates; D011448:Prostaglandin Antagonists; D017482:Receptors, Thromboxane; C056566:S 145; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D000410:Alanine Transaminase; C034364:ozagrel