Ishitsuka Yoichi, Moriuchi Hiroshi, Hatamoto Keita, Yang Changqing, Takase Junko, Golbidi Saeid, Irikura Mitsuru, Irie Tetsumi
Department of Clinical Chemistry and Informatics, Graduate school of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
J Pharm Pharmacol. 2004 Apr;56(4):513-20. doi: 10.1211/0022357023150.
An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and pulmonary vascular hyper-permeability. Although oleic acid lung injury is used as a model of acute respiratory distress syndrome (ARDS), the precise mechanisms of the lung injury are still unclear. We have investigated whether thromboxane A(2) (TXA(2)) participated in the lung injury and have evaluated the efficacy of ozagrel, a TXA(2) synthase inhibitor, on the lung injury in guinea-pigs. Oleic acid injection increased the plasma level of TXB(2), a stable metabolite of TXA(2), and the time-course of plasma TXB(2) was similar to that of the decreased partial oxygen pressure of arterial blood (Pao(2)) induced with oleic acid. Ozagrel administered intravenously 30 min before oleic acid injection prevented the decrease in Pao(2) and pulmonary vascular hyper-permeability. It also prevented increases in lactate dehydrogenase activity, a measure of lung cell injury, TXB(2 )and its weight ratio to 6-keto prostaglandin F(1alpha) in bronchoalveolar lavage fluid. Although ozagrel administered simultaneously with oleic acid ameliorated the decrease in Pao(2), post treatment showed little effect. We suggest that TXA(2) participated in the oleic acid lung injury, as an "early phase" mediator, and rapidly-acting TXA(2) synthase inhibitors were effective in the prevention of acute lung injury.
给动物静脉注射油酸可导致伴有低氧血症和肺血管通透性增高的肺损伤。尽管油酸肺损伤被用作急性呼吸窘迫综合征（ARDS）的模型，但肺损伤的确切机制仍不清楚。我们研究了血栓素A₂（TXA₂）是否参与肺损伤，并评估了TXA₂合酶抑制剂奥扎格雷对豚鼠肺损伤的疗效。注射油酸后，TXA₂的稳定代谢产物血浆TXB₂水平升高，血浆TXB₂的时间进程与油酸诱导的动脉血氧分压（Pao₂）降低相似。在注射油酸前30分钟静脉注射奥扎格雷可防止Pao₂降低和肺血管通透性增高。它还可防止乳酸脱氢酶活性升高（衡量肺细胞损伤的指标）、支气管肺泡灌洗液中TXB₂及其与6-酮前列腺素F₁α的重量比升高。尽管与油酸同时给药的奥扎格雷可改善Pao₂降低，但治疗后效果甚微。我们认为，TXA₂作为“早期”介质参与了油酸肺损伤，快速起效的TXA₂合酶抑制剂对预防急性肺损伤有效。
