Boichot E, Germain N, Emonds-Alt X, Advenier C, Lagente V
INSERM U456, Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes, Rennes, France.
Clin Exp Allergy. 1998 Oct;28(10):1299-305. doi: 10.1046/j.1365-2222.1998.00398.x.
Tachykinins, such as substance P, might be involved in the development of airway hyperresponsiveness and airway inflammation.
This study was designed to investigate the effects of the tachykinin NK1 receptor antagonist SR 140333 (Nolpitantium) and the NK2 receptor antagonist SR 48968 (Saredutant) on the activation of alveolar macrophages in the guinea-pig.
Guinea-pigs sensitized and challenged by ovalbumin administered by aerosol or naive guinea-pigs were exposed by aerosol to the neutral endopeptidase, phosphoramidon and, 15 min later, to substance P. Twenty-four hours later, bronchoalveolar lavages were performed and the cell composition of bronchoalveolar lavage fluids and the arachidonate release from alveolar macrophages stimulated in vitro with fMLP were evaluated.
Antigen challenge in sensitized guinea-pigs induced an increase in the total number of cells and granulocytes in the bronchoalveolar lavage fluids that was not reduced by pre-treatment of guinea-pigs with a single dose of SR 140333 or SR 48968 (1 mg/kg). Substance P exposure in phosphoramidon-pretreated guinea-pigs did not induce an increase in the total number of cells. In contrast, antigen or substance P exposure induced a significant increase in the in vitro fMLP-induced arachidonate release from alveolar macrophages. Pre-treatment of the guinea pigs with SR 140333 or SR 48968 did not reduce the increase in arachidonate release from fMLP-stimulated alveolar macrophages from sensitized and challenged guinea-pigs. Pre-treatment of the animals by SR 140333 and SR 48968 reduced the enhanced arachidonate release induced by fMLP from substance P-exposed guinea-pigs.
The present data demonstrate the importance of NK1- and NK2-receptor stimulation in the development of substance P-induced increased reactivity of alveolar macrophages.
速激肽，如P物质，可能参与气道高反应性和气道炎症的发生发展。
本研究旨在探讨速激肽NK1受体拮抗剂SR 140333（诺匹坦）和NK2受体拮抗剂SR 48968（沙瑞替坦）对豚鼠肺泡巨噬细胞活化的影响。
用卵清蛋白雾化致敏和激发的豚鼠或未致敏的豚鼠经雾化吸入中性内肽酶、磷酰胺素，15分钟后再吸入P物质。24小时后进行支气管肺泡灌洗，评估支气管肺泡灌洗液的细胞组成以及体外经fMLP刺激的肺泡巨噬细胞的花生四烯酸释放情况。
致敏豚鼠的抗原激发导致支气管肺泡灌洗液中细胞总数和粒细胞数量增加，单剂量SR 140333或SR 48968（1 mg/kg）预处理豚鼠不能使其减少。磷酰胺素预处理的豚鼠暴露于P物质后，细胞总数未增加。相反，抗原或P物质暴露导致体外经fMLP刺激的肺泡巨噬细胞花生四烯酸释放显著增加。用SR 140333或SR 48968预处理豚鼠不能减少致敏和激发豚鼠经fMLP刺激的肺泡巨噬细胞花生四烯酸释放的增加。用SR 140333和SR 48968预处理动物可减少P物质暴露豚鼠经fMLP诱导的花生四烯酸释放增强。
目前的数据表明NK1和NK2受体刺激在P物质诱导的肺泡巨噬细胞反应性增加的发生发展中具有重要作用。
