Pharmacological modulation of the effects of N‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine in guinea‐pigs: involvement of the arachidonic acid cascade
Pharmacological modulation of the effects of N‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine in guinea‐pigs: involvement of the arachidonic acid cascade
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N-甲酰基-L-甲硫氨酰-L-亮氨酰-L-苯丙氨酸对豚鼠作用的药理学调节：花生四烯酸级联的参与
DOI：
10.1111/j.1476-5381.1986.tb10267.x
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发表时间：
1986
影响因子：
7.3
通讯作者：
B. Vargaftig
中科院分区：
文献类型：
--
作者：
M. Boukili;Michel Bureau;V. Lagente;J. Lefort;A. Lellouch‐Tubiana;Evelyne Malanchère;B. Vargaftig
1豚鼠静脉注射趋化和促分泌肽N-甲酰-L-甲硫氨酰-L-亮氨酰-L-苯丙氨酸（FMLP; 0.3 - 30 μ g kg − 1）可诱导支气管收缩和剂量依赖性白细胞减少症，伴有轻度血小板减少症。在支气管收缩高峰时，未观察到肺部血小板聚集或胸部111In标记血小板显著蓄积的电子显微镜证据。2前列环素、血小板耗竭、血小板活化因子（PAF-acether）拮抗剂BN 52021或组胺H1-拮抗剂美托咪胺均不影响FMLP诱导的支气管收缩和白细胞减少。阿司匹林可抑制支气管收缩，但不能抑制白细胞减少，而肽-白三烯拮抗剂化合物FPL 55712和环加氧酶脂氧合酶抑制剂吲哚美辛仅在有限程度上减少支气管收缩。混合环加氧酶/脂氧合酶抑制剂化合物BW 755 C在使用最高剂量的FMLP时阻断支气管收缩非常有效，但未能干扰白细胞减少症。3 FMLP诱导的肺实质条剂量依赖性收缩伴随免疫反应性血栓素B2的形成，其量明显低于诱导收缩的等效浓度下外源性花生四烯酸形成的量。4 FMLP诱导的豚鼠肺条收缩未被美托洛尔或FPL 55712改变。吲哚美辛和阿司匹林可降低这些水平，阿司匹林与FPL 55712联合使用时降低幅度更大。BW 755 C抑制了所有浓度的FMLP的作用，而叔丁氧基羰基-L-甲硫氨酰基-L-亮氨酰基-L-苯丙氨酸（FMLP的化学类似物）使浓度响应曲线向右移位，而不降低获得的最大收缩。5目前的结果表明：（a）FMLP引起的支气管收缩不是由于血小板活化、环加氧酶依赖性机制或肽白三烯形成。阿司匹林和BW 755C的抑制作用涉及环加氧酶抑制以外的性质，这与吲哚美辛不同。(b)FMLP对肺实质条的收缩作用遵循与特定受体位点的相互作用，如叔丁氧基羰基-L-甲硫氨酰-L-亮氨酰-L-苯丙氨酸的有效性所示，并且涉及环加氧酶和脂氧合酶代谢物的联合作用。
1 The intravenous administration of the chemotactic and secretagogue peptide N‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine (FMLP; 0.3–30 μg 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. 2 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. 3 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. 4 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. 5 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.