Boukili M A, Bureau M, Lagente V, Lefort J, Lellouch-Tubiana A, Malanchère E, Vargaftig B B
Br J Pharmacol. 1986 Oct;89(2):349-59. doi: 10.1111/j.1476-5381.1986.tb10267.x.
The intravenous administration of the chemotactic and secretagogue peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 0.3-30 micrograms kg-1) to the guinea-pig induces bronchoconstriction and dose-dependent leukopenia accompanied by mild thrombocytopenia. No electron microscopic evidence of platelet aggregation in lungs or significant accumulation of 111In-labelled platelets in the thoracic region at the height of bronchoconstriction was noted. Bronchoconstriction and leukopenia induced by FMLP were not affected by prostacyclin, by platelet depletion, by the platelet-activating factor (Paf-acether) antagonist BN 52021 or by the histamine H1-antagonist mepyramine. Bronchoconstriction, but not leukopenia, was inhibited by aspirin, whereas the peptido-leukotriene antagonist compound FPL 55712 and the cyclo-oxygenase lipoxygenase inhibitor indomethacin reduced bronchoconstriction to a limited extent only. The mixed cyclo-oxygenase/lipoxygenase inhibitor compound BW 755C was very effective in blocking bronchoconstriction by the highest dose of FMLP used, but failed to interfere with leukopenia. FMLP-induced dose-dependent contraction of parenchymal lung strips was accompanied by the formation of immuno-reactive thromboxane B2 in amounts markedly less than those formed from exogenous arachidonic acid at concentrations equieffective in inducing contractions. FMLP-induced contractions of the guinea-pig lung strip were not modified by mepyramine nor by FPL 55712. They were reduced by indomethacin and aspirin and an even greater reduction was obtained with aspirin used in combination with FPL 55712. BW 755C suppressed the effects of all the concentrations of FMLP tested, whereas tert-butyloxy-carbonyl-L-methionyl-L-leucyl-L-phenylalanine, a chemical analogue of FMLP, displaced the concentration-response curve to the right, without reducing the maximal contraction obtained. The present results indicate that: (a) bronchoconstriction by FMLP is not due to platelet activation, to cyclo-oxygenase-dependent mechanisms or to peptido-leukotriene formation. The inhibitory effect of aspirin and BW 755C involves a property other than cyclo-oxygenase inhibition, which is not shared by indomethacin. (b) The contractile effects of FMLP on parenchymal lung strips follow an interaction with specific receptor sites, as shown by the effectiveness of tert-butyloxy-carbonyl-L-methionyl-L-leucyl-L-phenylalanine, and involves the combined effects of cyclo-oxygenase and lipoxygenase metabolites.
向豚鼠静脉注射趋化性及促分泌肽N-甲酰-L-蛋氨酰-L-亮氨酰-L-苯丙氨酸（FMLP；0.3 - 30微克/千克）可诱发支气管收缩和剂量依赖性白细胞减少，并伴有轻度血小板减少。在支气管收缩高峰期，未观察到肺部血小板聚集的电子显微镜证据，也未发现1铟标记的血小板在胸部区域有明显积聚。FMLP诱发的支气管收缩和白细胞减少不受前列环素、血小板耗竭、血小板激活因子（Paf-乙酰醚）拮抗剂BN 52021或组胺H1拮抗剂美吡拉敏的影响。阿司匹林可抑制支气管收缩，但不影响白细胞减少，而肽白三烯拮抗剂化合物FPL 55712和环氧化酶脂氧化酶抑制剂吲哚美辛仅在有限程度上减轻支气管收缩。混合环氧化酶/脂氧化酶抑制剂化合物BW 755C对所用最高剂量的FMLP诱发的支气管收缩有非常有效的阻断作用，但未能干扰白细胞减少。FMLP诱导的肺实质条带剂量依赖性收缩伴随着免疫反应性血栓素B2的形成，其形成量明显少于在诱导收缩效果相同的浓度下由外源性花生四烯酸形成的量。FMLP诱导的豚鼠肺条带收缩不受美吡拉敏或FPL 55712的影响。吲哚美辛和阿司匹林可使其收缩减弱，阿司匹林与FPL 55712联合使用时收缩减弱更明显。BW 755C可抑制所有测试浓度FMLP的作用，而FMLP的化学类似物叔丁氧羰基-L-蛋氨酰-L-亮氨酰-L-苯丙氨酸使浓度-反应曲线右移，但不降低最大收缩幅度。目前的结果表明：（a）FMLP诱发的支气管收缩并非由于血小板激活、环氧化酶依赖性机制或肽白三烯形成。阿司匹林和BW 755C的抑制作用涉及环氧化酶抑制以外的特性，吲哚美辛不具有此特性。（b）FMLP对肺实质条带的收缩作用遵循与特定受体位点的相互作用，如叔丁氧羰基-L-蛋氨酰-L-亮氨酰-L-苯丙氨酸的有效性所示，且涉及环氧化酶和脂氧化酶代谢产物的联合作用。
