Steudel W, Krämer H J, Degner D, Rosseau S, Schütte H, Walmrath D, Seeger W
Department of Internal Medicine, Justus-Liebig University, 35385 Giessen, Germany.
J Appl Physiol (1985). 1997 Jul;83(1):18-24. doi: 10.1152/jappl.1997.83.1.18.
In prior studies of perfused lungs, endotoxin priming markedly enhanced thromboxane (Tx) generation and Tx-mediated vasoconstriction in response to secondarily applied bacterial exotoxins. The present study addressed this aspect in more detail by employing precursor and intermediates of prostanoid synthesis and performing functional testing of vasoreactivity and measurement of product formation. Rabbit lungs were buffer perfused in the absence or presence of 10 ng/ml endotoxin. Repetitive intravascular bolus applications of free arachidonic acid provoked constant pulmonary arterial pressor responses and constant release reactions of TxA2 and prostaglandin (PG) I2 in nonprimed lungs. Within 60-90 min of endotoxin recirculation, which provoked progressive liberation of tumor necrosis factor-alpha but did not effect any hemodynamic changes by itself, both pressor responses and prostanoid release markedly increased, and both events were fully blocked by cyclooxygenase (Cyclo) inhibition with acetylsalicylic acid (ASA). The unstable intermediate PGG2 provoked moderate pressor responses, again enhanced by preceding endotoxin priming and fully suppressed by ASA. Vasoconstriction also occurred in response to the direct Cyclo product PGH2, again amplified after endotoxin pretreatment, together with markedly enhanced liberation of TxA2 and PGI2. In the presence of ASA, the priming-related increase in pressor responses and the prostanoid formation were blocked, but baseline vasoconstrictor responses corresponding to those in nonprimed lungs were maintained. Pressor responses to the stable Tx analog U-46619 were not significantly increased by endotoxin pretreatment, but some generation of TxA2 and PGI2 was also noted under these conditions. We conclude that endotoxin priming exerts profound effects on the lung vascular prostanoid metabolism, increasing the readiness to react with Tx-mediated vasoconstrictor responses to various stimuli, suggesting that enhanced Cyclo activity is an important underlying event.
在先前对灌注肺的研究中，内毒素预刺激显著增强了血栓素（Tx）的生成以及对二次应用细菌外毒素所产生的Tx介导的血管收缩。本研究通过使用前列腺素合成的前体和中间体，并进行血管反应性的功能测试以及产物生成的测量，更详细地探讨了这一方面。在不存在或存在10 ng/ml内毒素的情况下，用缓冲液灌注兔肺。在未预刺激的肺中，重复血管内推注游离花生四烯酸可引发恒定的肺动脉升压反应以及TxA2和前列腺素（PG）I2的恒定释放反应。在内毒素再循环60 - 90分钟内，这会引发肿瘤坏死因子-α的逐渐释放，但自身不会引起任何血流动力学变化，升压反应和类前列腺素释放均显著增加，并且这两个事件均被乙酰水杨酸（ASA）抑制环氧化酶（Cyclo）完全阻断。不稳定中间体PGG2引发中度升压反应，同样在先前的内毒素预刺激后增强，并被ASA完全抑制。对直接的Cyclo产物PGH2也会发生血管收缩，在内毒素预处理后再次放大，同时TxA2和PGI2的释放显著增强。在存在ASA的情况下，预刺激相关的升压反应增加和类前列腺素形成被阻断，但与未预刺激肺中的反应相对应的基线血管收缩反应得以维持。内毒素预处理并未显著增加对稳定的Tx类似物U - 46619的升压反应，但在这些条件下也观察到了一些TxA2和PGI2的生成。我们得出结论，内毒素预刺激对肺血管类前列腺素代谢产生深远影响，增加了对各种刺激以Tx介导的血管收缩反应作出反应的准备状态，表明增强的Cyclo活性是一个重要的潜在事件。
