Fornhem C, Kumlin M, Lundberg J M, Alving K
Dept of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Eur Respir J. 1995 Jul;8(7):1100-9. doi: 10.1183/09031936.95.08071100.
The aim of this study was to develop a novel model for studies of mediator mechanisms involved in the late asthmatic reaction in the lower airways, by using the sensitized pig. The release of histamine and cysteinyl-containing leukotrienes (cys-LTs), as well as the levels of inflammatory cells in blood and bronchoalveolar lavage fluid, were determined and their relationship to plasma cortisol levels and pulmonary airways obstruction was noted. Specific-pathogen free pigs were actively sensitized with Ascaris suum allergen, and one group of animals was treated with a cortisol-synthesis inhibitor (metyrapone) by constant intravenous infusion. Ascaris suum allergen was nebulized into the lower airways and total lung resistance, blood leucocyte count and urinary levels of methylhistamine and leukotriene E4 (LTE4) were followed for 8 h, whereafter bronchoalveolar lavage was performed for analysis of leucocytes. An increase in urinary methylhistamine and LTE4 was seen during the acute allergic reaction in both groups of pigs. Metyrapone treatment prolonged the acute release of histamine, and this was seen together with a prolonged acute bronchoconstrictor response. In metyrapone-treated pigs, a continuous release over 8 h was seen for cys-LTs, but not for histamine. A late blood eosinophilia was also seen in metyrapone-treated animals, starting 4-6 h after allergen challenge. Late cys-LT release and eosinophilia were absent in non-metyrapone-treated animals. These results suggest that allergen-induced late release of cys-LTs as well as blood eosinophilia occur simultaneously with late-phase airways obstruction in the pig, and that all these reactions are prevented by high levels of endogenous cortisol.
本研究的目的是通过使用致敏猪，开发一种用于研究下呼吸道迟发性哮喘反应中介导机制的新型模型。测定组胺和含半胱氨酰白三烯（cys-LTs）的释放，以及血液和支气管肺泡灌洗液中炎症细胞的水平，并记录它们与血浆皮质醇水平和肺气道阻塞的关系。无特定病原体猪用猪蛔虫变应原进行主动致敏，一组动物通过持续静脉输注给予皮质醇合成抑制剂（甲吡酮）。将猪蛔虫变应原雾化至下呼吸道，随访8小时观察总肺阻力、血白细胞计数以及尿甲基组胺和白三烯E4（LTE4）水平，之后进行支气管肺泡灌洗以分析白细胞。两组猪在急性过敏反应期间尿甲基组胺和LTE4均增加。甲吡酮治疗延长了组胺的急性释放，同时伴有延长的急性支气管收缩反应。在甲吡酮治疗的猪中，观察到cys-LTs在8小时内持续释放，但组胺没有。在甲吡酮治疗的动物中还观察到迟发性血嗜酸性粒细胞增多，在变应原激发后4 - 6小时开始。未用甲吡酮治疗的动物中不存在迟发性cys-LT释放和嗜酸性粒细胞增多。这些结果表明，在猪中，变应原诱导的cys-LTs迟发性释放以及血嗜酸性粒细胞增多与迟发性气道阻塞同时发生，并且所有这些反应都被高水平的内源性皮质醇所阻止。
