Solèr M, Sielczak M, Abraham W M
Division of Pulmonary Disease, Mount Sinai Medical Center, Miami Beach, Florida 33140.
Pulm Pharmacol. 1990;3(1):9-15. doi: 10.1016/0952-0600(90)90003-2.
The effects of a new bradykinin-antagonist, NPC-567 (D-Arg [hydroxyproline3, D-phenylalanine7] bradykinin) were studied on antigen-induced airway hyperresponsiveness and inflammation in allergic sheep (n = 7). Specific lung resistance (sRL) was used to assess airway responses to inhaled Ascaris suum-antigen. Airway responsiveness was determined from slopes of cumulative dose-response-curves (DRC) to inhaled carbachol. DRCs were performed at baseline and 2 h after an inhalation challenge with antigen. Bronchoalveolar lavage, performed before antigen-challenge and after the post-challenge DRC was used to assess antigen-induced inflammatory changes. For these studies NPC-567 was given as an aerosol (20 breaths, 10 mg/ml) 30 min before antigen challenge and (400 breaths, 2 mg/ml) co-administered with the Ascaris suum antigen. The immediate increase in specific lung resistance (sRL) after antigen challenge was not different with (232 +/- 152% increase) or without drug pre-treatment (148 +/- 129% increase). In the control trial, antigen challenge led to an increase in slope of the post-challenge DRC by 123 +/- 118% compared to baseline (p less than 0.05). This hyperresponsiveness was almost completely prevented by NPC-567 (increase in slope 32 +/- 64%, p less than 0.05 vs. control). Similarly, the antigen-induced inflammatory response, characterized by a significant 3.3-fold increase over baseline in the percentage of neutrophils in the control-experiment, was blocked by the bradykinin-antagonist. These results suggest that bradykinin may be involved in the pathogenesis of antigen-induced airway inflammation and the consequent development of airway hyperresponsiveness in sheep.
研究了一种新型缓激肽拮抗剂NPC - 567（D - 精氨酸[羟脯氨酸3，D - 苯丙氨酸7]缓激肽）对变应性绵羊（n = 7）抗原诱导的气道高反应性和炎症的影响。采用特异性肺阻力（sRL）评估气道对吸入猪蛔虫抗原的反应。通过吸入卡巴胆碱的累积剂量反应曲线（DRC）斜率来测定气道反应性。在基线时以及抗原吸入激发后2小时进行DRC测定。在抗原激发前和激发后DRC测定后进行支气管肺泡灌洗，以评估抗原诱导的炎症变化。在这些研究中，NPC - 567在抗原激发前30分钟以气雾剂形式给予（20次呼吸，10mg/ml），并与猪蛔虫抗原共同给予（400次呼吸，2mg/ml）。抗原激发后特异性肺阻力（sRL）的即刻增加在药物预处理组（增加232±152%）和未预处理组（增加148±129%）之间无差异。在对照试验中，与基线相比，抗原激发导致激发后DRC斜率增加123±118%（p<0.05）。NPC - 567几乎完全预防了这种高反应性（斜率增加32±64%，与对照组相比p<0.05）。同样，缓激肽拮抗剂阻断了抗原诱导的炎症反应，在对照实验中，其特征为中性粒细胞百分比比基线显著增加3.3倍。这些结果表明，缓激肽可能参与了绵羊抗原诱导的气道炎症发病机制以及随之而来的气道高反应性的发展。
