Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
Clin Sci (Lond). 2013 Dec;125(11):533-42. doi: 10.1042/CS20130092.
One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70% of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management.
变应性哮喘的一个特征，即 EAR（早期过敏反应），在常用的小鼠模型中并不存在。因此，我们在豚鼠体内变应性气道炎症模型中研究了 EAR 中涉及的介质。动物通过单次 OVA（卵清蛋白）/明矾注射进行致敏，并在第 14 天用雾化 OVA 进行挑战。在第 15 天，使用强迫振荡技术在 OVA 或 MCh（乙酰甲胆碱）挑战后评估气道阻力，并准备肺组织进行组织学检查。使用主要肥大细胞介质的抑制剂[组胺（吡拉明）和 CysLTs（半胱氨酰白三烯）（孟鲁司特）和前列腺素（吲哚美辛）]研究肥大细胞介质的贡献。OVA 致敏和挑战的动物对 MCh 表现出 AHR（气道高反应性），并且肺组织嗜酸性粒细胞炎症。抗原挑战诱导致敏动物发生强烈的 EAR。单一化合物治疗，或吲哚美辛与吡拉明或孟鲁司特联合治疗，均不能降低抗原引起的气道阻力。相比之下，吡拉明与孟鲁司特联合治疗，或三联抑制剂治疗，可减轻约 70%的 EAR。我们得出结论，与人类一样，豚鼠变应性炎症模型表现出 EAR 和 AHR，支持其适合体内鉴定有助于哮喘发展的肥大细胞介质。此外，已知的肥大细胞介质组胺和白三烯是 EAR 的主要贡献者。该数据还进一步支持了这样的概念，即选择性关键介质抑制剂的联合治疗可能改善哮喘管理。
