Discovery & Development Laboratory 2, Taiho Pharmaceutical Co. Ltd., 3, Ohkubo, Tsukuba, Ibaraki 300-2611, Japan.
Eur J Pharmacol. 2011 Sep 30;667(1-3):389-95. doi: 10.1016/j.ejphar.2011.05.041. Epub 2011 Jun 1.
We investigated the role of hematopoietic prostaglandin D synthase (H-PGDS) in biphasic nasal obstruction in allergic rhinitis using a new specific inhibitor, (N-methoxy-N-methyl)-4-(5-benzoylbenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide hydrochloride (TAS-204). First, we developed a novel guinea pig model of allergic rhinitis. Guinea pigs sensitized to ovalbumin without adjuvant were challenged with intranasal exposure to ovalbumin once a week. After the 3rd antigen challenge, they exhibited biphasic nasal obstruction. Additionally, analysis of nasal lavage fluid revealed an increase in the level of prostaglandin D(2) in both early and late phases. Treatment with oral TAS-204 for 15 days during the period of antigen challenges suppressed increases in nasal airway resistance in both phases. It is noteworthy that the late phase nasal obstruction was almost completely abrogated by inhibiting H-PGDS alone. Eosinophil infiltration in nasal lavage fluid and nasal hyperresponsiveness to histamine was also reduced by TAS-204 administration. These findings suggest that H-PGDS plays a critical role in the development of allergic rhinitis, especially in the induction of late phase nasal obstruction.
我们使用一种新型的特异性抑制剂（N-甲氧基-N-甲基）-4-（5-苯甲酰苯并咪唑-2-基）-3,5-二甲基吡咯-2-甲酰胺盐酸盐（TAS-204），研究了造血前列腺素 D 合酶（H-PGDS）在变应性鼻炎双相性鼻阻塞中的作用。首先，我们建立了一种新型的变应性鼻炎豚鼠模型。无佐剂卵清蛋白致敏的豚鼠每周接受一次鼻腔内卵清蛋白暴露。在第 3 次抗原挑战后，它们表现出双相性鼻阻塞。此外，鼻灌洗液分析显示，在早期和晚期，前列腺素 D（2）的水平均增加。在抗原挑战期间口服 TAS-204 治疗 15 天，可抑制两个阶段的鼻气道阻力增加。值得注意的是，仅抑制 H-PGDS 就可使晚期鼻阻塞几乎完全消除。TAS-204 给药还可减少鼻灌洗液中的嗜酸性粒细胞浸润和对组胺的鼻高反应性。这些发现表明 H-PGDS 在变应性鼻炎的发展中，特别是在诱导晚期鼻阻塞中发挥关键作用。
