Lefort J, Rotilio D, Vargaftig B B
Br J Pharmacol. 1984 Jul;82(3):565-75. doi: 10.1111/j.1476-5381.1984.tb10795.x.
Intra-arterial injections of platelet-activating factor (Paf-acether, 10-300 ng) to the perfused guinea-pig lung induced a dose-related bronchoconstriction, followed by contraction of the rat aorta superfused with the lung effluent, indicating the release of thromboxane A2 (TXA2) activity. These effects were matched with injections of bradykinin (Bk) at 100-1000 ng, leukotriene C4(LTC4) at 10-300 ng or arachidonic acid (AA) at 30-300 micrograms. Repeated doses of Paf-acether led to a specific desensitization of the release of TXA2, under conditions where Bk, LTC4 and arachidonic acid retained their ability to release TXA2. Bronchoconstriction and the release of TXA2 induced by Paf-acether were suppressed when the lungs were perfused with acetylsalicylic acid, but not with salicylic acid. The phospholipase A2 inhibitor, p-bromophenacyl bromide suppressed the release of TXA2 by Bk, but did not interfere with its formation from AA, nor with its release with Paf-acether and LTC4. The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibited to a similar extent the release of TXA2 by Bk, LTC4 and Paf-acether but also reduced directly the formation of TXA2 from arachidonic acid, invalidating its use as a specific antilipoxygenase agent. The leukotriene C4/D4 antagonist, FPL 55712, suppressed the TXA2 releasing effects of LTC4, and was completely inactive against Paf-acether, Bk or arachidonic acid. The aerosol of Paf-acether was tested in the anaesthetized guinea-pig and resulted in bronchoconstriction, unaccompanied by thrombocytopenia. Unlike bronchoconstriction induced by intravenous Paf-acether, which is refractory to cyclo-oxygenase inhibitors, the effects of the aerosol were suppressed by aspirin. Platelet depletion, which blocks the intravenous effects of Paf-acether, failed to interfere with those of the aerosol. Paf-acether induced a marked contraction of the superfused guinea-pig isolated parenchyma lung strip, which was followed by total and irreversible desensitization to itself. The contractile effect was not inhibited by aspirin or indomethacin, atropine, mepyramine, methysergide, phenoxybenzamine or propranolol, indicating that cyclo-oxygenase products, cholinergic stimuli, histamine, 5-hydroxytryptamine and catecholamine mechanisms are not involved. Our results indicate that Paf-acether interacts with pulmonary sites distinct from those for Bk, LTC4 or AA, since no cross-desensitization between Paf-acether and the other agonists was noted, p-bromophenacyl bromide inhibited Bk only and FPL 55712 inhibited only LTC4. The phospholipase A2 involved with the release of the arachidonate needed for the formation of TXA2 by Paf-acether or LTC4-stimulated lungs may differ from the enzyme accounting for its formation by Bk. The cellular sites with which Paf-acether interacts may also be distinct and less readily accessible to p-bromophenacyl bromide.
向灌注的豚鼠肺内动脉注射血小板活化因子（血小板激活因子，10 - 300纳克）可诱导剂量相关的支气管收缩，随后用肺流出液灌注的大鼠主动脉发生收缩，这表明血栓素A2（TXA2）活性被释放。这些效应与注射100 - 1000纳克的缓激肽（Bk）、10 - 300纳克的白三烯C4（LTC4）或30 - 300微克的花生四烯酸（AA）时的效应相当。重复给予血小板激活因子会导致TXA2释放出现特异性脱敏，而此时Bk、LTC4和花生四烯酸仍保留其释放TXA2的能力。当用乙酰水杨酸灌注肺时，血小板激活因子诱导的支气管收缩和TXA2释放受到抑制，但用水杨酸灌注时则无此作用。磷脂酶A2抑制剂对溴苯甲酰溴抑制Bk诱导的TXA2释放，但不干扰由AA形成TXA2，也不干扰其由血小板激活因子和LTC4诱导的释放。脂氧合酶抑制剂去甲二氢愈创木酸对Bk、LTC4和血小板激活因子诱导的TXA2释放有相似程度的抑制作用，但也直接减少了花生四烯酸形成TXA2，使其不能作为特异性抗脂氧合酶药物使用。白三烯C4/D4拮抗剂FPL 55712抑制LTC4释放TXA2的作用，对血小板激活因子、Bk或花生四烯酸完全无活性。在麻醉的豚鼠中测试了血小板激活因子气雾剂，结果导致支气管收缩，且不伴有血小板减少。与静脉注射血小板激活因子诱导的支气管收缩不同，后者对环氧化酶抑制剂无反应，气雾剂的作用被阿司匹林抑制。血小板耗竭可阻断血小板激活因子的静脉作用，但不影响气雾剂的作用。血小板激活因子可使灌注的豚鼠离体实质肺条显著收缩，随后对其自身产生完全且不可逆的脱敏。收缩作用不受阿司匹林、吲哚美辛、阿托品、美吡拉敏、甲基麦角新碱、酚苄明或普萘洛尔的抑制，这表明环氧化酶产物、胆碱能刺激、组胺、5 - 羟色胺和儿茶酚胺机制均未参与。我们的结果表明，血小板激活因子与肺中不同于Bk、LTC4或AA的部位相互作用，因为未观察到血小板激活因子与其他激动剂之间的交叉脱敏，对溴苯甲酰溴仅抑制Bk，FPL 557l2仅抑制LTC4。参与由血小板激活因子或LTC4刺激的肺形成TXA2所需花生四烯酸释放的磷脂酶A2可能与由Bk形成TXA2时的酶不同。血小板激活因子相互作用的细胞部位也可能不同，且对溴苯甲酰溴的可及性较低。
