Role of Thromboxane Derived from COX-1 and -2 in Hepatic Microcirculatory Dysfunction during endotoxemia in Mice

Hiroyuki Katagiri, Yoshiya Ito, Ken Ichiro Ishii, Izumi Hayashi, Makoto Suematsu, Shohei Yamashina, Takahiko Murata, Shuh Narumiya, Akira Kakita, Masataka Majima

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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 TXA2 in leukocyte endothelial interaction during endotoxemia. The present study was conducted to investigate the role of TXA2 as well as that of COX in lipopolysaccharide (LPS)-induced hepatic microcirculatory dysfunction in male C57B1/6 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 (TNFα) also increased. LPS raised the TXB 2 level in the perfusate from isolated perfused liver. A TXA 2 synthase inhibitor, OKY-046, and a TXA2 receptor antagonist, S-1452, reduced LPS-induced hepatic microcirculatory dysfunction by inhibiting TNFα 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 TNFα. The effects of the COX inhibitors on hepatic responses to LPS exhibited results similar to those obtained with TXA2 synthase inhibitor, and TXA2 receptor antagonist. In conclusion, these results suggest that TXA2 is involved in LPS-induced hepatic microcirculatory dysfunction partly through the release of TNFα, and that TXA2 derived from COX-1 and COX-2 could be responsible for the microcirculatory dysfunction during endotoxemia.

Original languageEnglish
Pages (from-to)139-150
Number of pages12
JournalHepatology
Volume39
Issue number1
DOIs
Publication statusPublished - 2004 Jan

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Cyclooxygenase 1
Endotoxemia
Thromboxanes
Cyclooxygenase 2
Lipopolysaccharides
Liver
Tumor Necrosis Factor-alpha
Cyclooxygenase Inhibitors
Prostaglandin-Endoperoxide Synthases
Alanine Transaminase
S 145
Leukocytes
Thromboxane Receptors
Cyclooxygenase 2 Inhibitors
Intercellular Adhesion Molecule-1
Microvessels
Knockout Mice
Indomethacin
Prostaglandins
Fluorescence

ASJC Scopus subject areas

  • Hepatology

Cite this

Katagiri, H., Ito, Y., Ishii, K. I., Hayashi, I., Suematsu, M., Yamashina, S., ... Majima, M. (2004). Role of Thromboxane Derived from COX-1 and -2 in Hepatic Microcirculatory Dysfunction during endotoxemia in Mice. Hepatology, 39(1), 139-150. https://doi.org/10.1002/hep.20000

Role of Thromboxane Derived from COX-1 and -2 in Hepatic Microcirculatory Dysfunction during endotoxemia in Mice. / Katagiri, Hiroyuki; Ito, Yoshiya; Ishii, Ken Ichiro; Hayashi, Izumi; Suematsu, Makoto; Yamashina, Shohei; Murata, Takahiko; Narumiya, Shuh; Kakita, Akira; Majima, Masataka.

In: Hepatology, Vol. 39, No. 1, 01.2004, p. 139-150.

Research output: Contribution to journalArticle

Katagiri, H, Ito, Y, Ishii, KI, Hayashi, I, Suematsu, M, Yamashina, S, Murata, T, Narumiya, S, Kakita, A & Majima, M 2004, 'Role of Thromboxane Derived from COX-1 and -2 in Hepatic Microcirculatory Dysfunction during endotoxemia in Mice', Hepatology, vol. 39, no. 1, pp. 139-150. https://doi.org/10.1002/hep.20000
Katagiri, Hiroyuki ; Ito, Yoshiya ; Ishii, Ken Ichiro ; Hayashi, Izumi ; Suematsu, Makoto ; Yamashina, Shohei ; Murata, Takahiko ; Narumiya, Shuh ; Kakita, Akira ; Majima, Masataka. / Role of Thromboxane Derived from COX-1 and -2 in Hepatic Microcirculatory Dysfunction during endotoxemia in Mice. In: Hepatology. 2004 ; Vol. 39, No. 1. pp. 139-150.
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