Abraham W M, Ahmed A, Cortes A, Sielczak M W, Hinz W, Bouska J, Lanni C, Bell R L
Harry Pearlman Biomedical Research Institute, Mount Sinai Medical Center, Miami Beach, FL 33140.
Eur J Pharmacol. 1992 Jul 7;217(2-3):119-26. doi: 10.1016/0014-2999(92)90829-s.
Leukotrienes are thought to be involved in allergen-induced airway responses. To test this hypothesis we used a newly described 5-lipoxygenase inhibitor, zileuton, and examined its effect on antigen-induced early and late bronchial responses, airway inflammation and airway hyperresponsiveness in allergic sheep. Early and late responses were determined by measuring specific lung resistance (SRL) before and serially for 8 h after antigen challenge. Airway inflammation was assessed by bronchoalveolar lavage performed before, 8 h after and 24 h after antigen challenge. Airway responsiveness was measured before and 24 h after challenge by determining the dose of inhaled carbachol that caused a 400% increase in SRL (PD400%). The sheep (n = 8) were challenged with Ascaris suum antigen once after vehicle treatment (methylcellulose) and once after treatment with zileuton (10 mg/kg in methylcellulose, p.o.) given 2 h before antigen challenge. Trials were separated by at least 21 days. Zileuton had no effect on the early bronchoconstrictor response to antigen but the drug inhibited the late bronchial response by 55% (P less than 0.05). Unlike the control trial, there was no significant increase in bronchoalveolar lavage eosinophils at 8 h post challenge in the zileuton-treated sheep. Furthermore, zileuton treatment blocked (P less than 0.05) the airway hyperresponsiveness seen 24 h after challenge. Ex vivo formation of leukotriene B4 was inhibited over several hours after a single oral dose of zileuton, indicating that the compound was acting as a 5-lipoxygenase inhibitor in vivo. These results suggest that 5-lipoxygenase metabolites contribute to allergen-induced late responses, airway inflammation and airway hyperresponsiveness in this animal model of asthma.
白三烯被认为参与了变应原诱导的气道反应。为了验证这一假设，我们使用了一种新描述的5-脂氧合酶抑制剂齐留通，并研究了其对变应性绵羊抗原诱导的早期和晚期支气管反应、气道炎症和气道高反应性的影响。通过在抗原激发前及激发后连续8小时测量比肺阻力（SRL）来确定早期和晚期反应。通过在抗原激发前、激发后8小时和24小时进行支气管肺泡灌洗来评估气道炎症。通过测定引起SRL增加400%的吸入卡巴胆碱剂量（PD400%）来测量激发前和激发后24小时的气道反应性。绵羊（n = 8）在给予赋形剂（甲基纤维素）治疗后用猪蛔虫抗原激发一次，在抗原激发前2小时给予齐留通（10 mg/kg溶于甲基纤维素，口服）治疗后再激发一次。试验间隔至少21天。齐留通对抗原诱导的早期支气管收缩反应没有影响，但该药物将晚期支气管反应抑制了55%（P<0.05）。与对照试验不同，在接受齐留通治疗的绵羊中，激发后8小时支气管肺泡灌洗嗜酸性粒细胞没有显著增加。此外，齐留通治疗可阻断（P<0.05）激发后24小时出现的气道高反应性。单次口服齐留通后数小时内，白三烯B4的体外形成受到抑制，表明该化合物在体内作为一种5-脂氧合酶抑制剂发挥作用。这些结果表明，在这个哮喘动物模型中，5-脂氧合酶代谢产物促成了变应原诱导的晚期反应、气道炎症和气道高反应性。
