Role of thromboxane derived from COX-1 and-2 in hepatic microcirculatory dysfunction during endotoxemia in mice
Role of thromboxane derived from COX-1 and-2 in hepatic microcirculatory dysfunction during endotoxemia in mice
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DOI：
10.1002/hep.20000
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发表时间：
2004-01-01
期刊：
影响因子：
13.5
通讯作者：
Majima, M
中科院分区：
文献类型：
--
作者：
Katagiri, H;Ito, Y;Majima, M
虽然血栓素（TXs）的合成受环氧合酶（考克斯）的调节，已被认为可促进肝脏炎症，但对内毒素血症时TXA 2在白细胞内皮细胞相互作用中的作用知之甚少。本研究旨在探讨血栓素A（2）和考克斯在脂多糖（LPS）诱导的雄性C57 B1/6小鼠肝脏微循环障碍中的作用。我们在活体荧光显微镜研究中观察到，LPS引起粘附在肝微血管和非灌注血窦上的白细胞显著积聚。血清丙氨酸转氨酶（ALT）和肿瘤坏死因子α（TNF α）水平也升高。LPS使离体肝脏灌流液中TXB_2水平升高。TXA（2）合成酶抑制剂OKY-046和TXA（2）受体拮抗剂S-1452通过抑制TNF α的产生来减轻LPS诱导的肝微循环功能障碍。OKY-046抑制LPS处理的肝脏中细胞间粘附分子（ICAM）-1的表达。在血栓素前列腺素受体敲除小鼠中，与野生型小鼠相比，肝脏对LPS的反应最小化。此外，选择性考克斯-1抑制剂SC-560、选择性考克斯-2抑制剂NS-398和吲哚美辛显著减弱了对LPS的肝反应，包括微循环功能障碍和ALT和TNF α的释放。考克斯抑制剂对LPS诱导的肝脏反应的影响与TXA（2）合成酶抑制剂和TXA（2）受体拮抗剂相似。这些结果表明，TXA（2）部分通过释放TNF α参与了LPS诱导的肝脏微循环功能障碍，考克斯-1和考克斯-2来源的TXA（2）可能是内毒素血症时微循环功能障碍的原因。
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 dysfimction 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 (TNFalpha) also increased. LPS raised the TXB2 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 dysfimction by inhibiting TNFalpha 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 TNFalpha. 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 TNFalpha, and that TXA(2) derived from COX-1 and COX-2 could be responsible for the microcirculatory dysfunction during endotoxemia.