Ishiguro S, Arii S, Monden K, Adachi Y, Funaki N, Higashitsuji H, Fujita S, Furutani M, Mise M, Kitao T
First Department of Surgery, Faculty of Medicine, Kyoto University, Japan.
Hepatology. 1994 Nov;20(5):1281-6.
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/10(6) cells and 13.80 +/- 1.60 x 10(3) 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 10(3) 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/10(6) cells and 3.65 +/- 0.39 x 10(3) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
研究了肝血窦内皮细胞中血栓素A2受体的存在情况，并检测了其在内毒素诱导的肝损伤中的致病作用。使用特异性血栓素A2受体拮抗剂[3H]S - 145通过结合试验测定该受体。结合的Scatchard分析表明存在一类单一的高亲和力结合位点，解离常数为5.00±0.96 nmol/L，最大结合量为22.85±2.71 fmol/10(6)个细胞，每个细胞有13.80±1.60×10(3)个结合位点。在细胞制备过程中添加环氧化酶抑制剂吲哚美辛可分别使最大结合值和结合位点数量增加至37.34±3.01和22.50±1.80×10(3)个位点/细胞。该结合可被各种血栓素A2类似物如ONO - 3708和STA2取代，但不能被其他前列腺素有效竞争。内毒素注射使肝血窦内皮细胞中的解离常数、最大结合量和结合位点数量分别降至3.49±0.87 nmol/L、6.03±0.64 fmol/10(6)个细胞和3.65±0.39×10(3)个位点/细胞。在内毒素治疗前添加环氧化酶抑制剂和库普弗细胞抑制剂可显著防止血栓素A2受体数量的减少。这些作用可能是由于通过防止血栓素A2产生减少了激动剂诱导的血栓素A2受体内化。预先给予环氧化酶抑制剂和血栓素A2受体拮抗剂均可减轻内毒素诱导的肝损伤程度。（摘要截断于250字）
