Identification of the thromboxane A2 receptor in hepatic sinusoidal endothelial cells and its role in endotoxin-induced liver injury in rats

Satoshi Ishiguro, Shigeki Arii, Kazunobu Monden, Yukito Adachi, Naomi Funaki, Hiroaki Higashitsuji, Shin Ichi Fujita, Masaharu Furutani, Masahiro Mise, Tadahiro Kitao, Toshio Nakamura, Fumitaka Ushikubi, Ken Ichi Nakamura, Shuh Narumiya, Katsuhiko Enomoto, Tousei Ohmura, Michio Mori, Masayuki Imamura

    Research output: Contribution to journalArticle

    Abstract

    The presence of the thromboxane A2 receptor in sinusoidal endothelial cells was investigated and its pathogenic role in endotoxin-induced liver injury examined. The receptor was measured with a binding assay using a specific thromboxane A2 receptor antagonist, [3H]S-145. Scatchard analysis of the binding indicated the presence of a single class of high-affinity binding sites with a dissociation constant of 5.00 ± 0.96 nmol/L, a maximal binding of 22.85 ± 2.71 fmol/106 cells and 13.80 ± 1.60 x 103 binding sites per cell. The addition of a cyclooxygenase inhibitor, indomethacin, during the cell preparation increased the maximal binding value and the number of binding sites of 37.34 ± 3.01 and 22.50 ± 1.80 x 103 sites/cell, respectively. The binding was displaced by various thromboxane A2 analogs such as ONO-3708 and STA2 but was not effectively competed for by other prostaglandins. Endotoxin injection reduced dissociation constant, maximal binding and the number of binding sites in sinusoidal endothelial cells to 3.49 ± 0.87 nmol/L, 6.03 ± 0.64 fmol/106 cells and 3.65 ± 0.39 x 103 sites/cell, respectively. A cyclooxygenase inhibitor and a Kupffer cell inhibitor added before endotoxin treatment significantly prevented the reduction in the number of thromboxane A2 receptors. It is possible that these effects were due to a reduction in the agonist-induced internalization of the thromboxane A2 receptor brought about by the prevention of thromboxane A2 production. Preadministration of both a cyclooxygenase inhibitor and a thromboxane A2 receptor antagonist attenuated the degree of endotoxin-induced liver injury. These findings indicated that the thromboxane A2-thromboxane A2 receptor system in the hepatic sinusoids plays a significant role in the pathogenesis of endotoxin-dependent liver damage.

    Original languageEnglish (US)
    Pages (from-to)1281-1286
    Number of pages6
    JournalHepatology
    Volume20
    Issue number5
    DOIs
    StatePublished - Nov 1 1994

    ASJC Scopus subject areas

    • Hepatology

    Fingerprint Dive into the research topics of 'Identification of the thromboxane A<sub>2</sub> receptor in hepatic sinusoidal endothelial cells and its role in endotoxin-induced liver injury in rats'. Together they form a unique fingerprint.

  • Cite this

    Ishiguro, S., Arii, S., Monden, K., Adachi, Y., Funaki, N., Higashitsuji, H., Fujita, S. I., Furutani, M., Mise, M., Kitao, T., Nakamura, T., Ushikubi, F., Nakamura, K. I., Narumiya, S., Enomoto, K., Ohmura, T., Mori, M., & Imamura, M. (1994). Identification of the thromboxane A2 receptor in hepatic sinusoidal endothelial cells and its role in endotoxin-induced liver injury in rats. Hepatology, 20(5), 1281-1286. https://doi.org/10.1016/0270-9139(94)90769-2