Hematology/Respiratory Medicine, Kanazawa University Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa, Ishikawa, Japan.
Hematology/Respiratory Medicine, Kanazawa University Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa, Ishikawa, Japan.
Pulm Pharmacol Ther. 2018 Feb;48:62-70. doi: 10.1016/j.pupt.2017.09.003. Epub 2017 Sep 22.
A feature of cough variant asthma is a heightened cough response to bronchoconstriction. The mediators of this response are unknown. This study was designed to elucidate the role of lipid mediators in bronchoconstriction-triggered cough response in an experimental animal model. We examined the influence of bronchoconstriction on cell components and mediators including prostaglandin E (PGE) in bronchoalveolar lavage fluid (BALF). We studied the cough response to bronchoconstriction (CRB) by measuring the correlation between the increase in enhanced pause (Penh), an index of bronchoconstriction, and cough counts induced by methacholine (Mch) inhalation in conscious guinea pigs. We then examined the effects of intraperitoneal pretreatment with 16, 16-dimethyl-prostaglandin E (dm-PGE) on CRB and cough counts. The total number of cells and cell components in the BALF were not influenced by bronchoconstriction. While levels of PGE, prostaglandin I, and cysteinyl leukotrienes were significantly increased, levels of prostaglandin D, thromboxane B, and substance P in the BALF were not. Dm-PGE significantly decreased the Mch-induced increase in Penh. Following bronchoconstriction by additional Mch inhalation, dm-PGE produced an increase in CRB and cough counts in a dose-dependent manner. Additionally, the heightened CRB following dm-PGE treatment was suppressed by pretreatment with PGE receptor (E-prostanoid EP) -1 and EP-3 antagonists in a dose-dependent manner, but not by EP-2 and EP-4 antagonists. The EP-1 antagonist also decreased cough counts. These results suggest that PGE acts as an exacerbating factor for bronchoconstriction-triggered cough. EP1 and EP3 may provide new therapeutic targets for cough variant asthma.
咳嗽变异性哮喘的一个特征是对支气管收缩的咳嗽反应增强。这种反应的介质尚不清楚。本研究旨在阐明在实验动物模型中，脂类介质在支气管收缩引发的咳嗽反应中的作用。我们检查了支气管收缩对包括前列腺素 E（PGE）在内的细胞成分和介质在支气管肺泡灌洗液（BALF）中的影响。我们通过测量增强呼气暂停（Penh）的增加与乙酰甲胆碱（Mch）吸入引起的咳嗽次数之间的相关性来研究支气管收缩诱发的咳嗽反应（CRB），Penh 是支气管收缩的指标。然后，我们检查了腹腔内预先用 16,16-二甲基前列腺素 E（dm-PGE）预处理对 CRB 和咳嗽次数的影响。支气管收缩并未影响 BALF 中的总细胞数和细胞成分。尽管 PGE、前列腺素 I 和半胱氨酰白三烯的水平显著增加，但 BALF 中的前列腺素 D、血栓素 B 和 P 物质的水平没有增加。dm-PGE 显著降低了 Mch 诱导的 Penh 增加。在通过额外的 Mch 吸入引起支气管收缩后，dm-PGE 以剂量依赖性方式增加 CRB 和咳嗽次数。此外，dm-PGE 处理后增强的 CRB 被 PGE 受体（E-前列腺素 EP）-1 和 EP-3 拮抗剂以剂量依赖性方式抑制，但不受 EP-2 和 EP-4 拮抗剂的抑制。EP-1 拮抗剂也降低了咳嗽次数。这些结果表明 PGE 作为支气管收缩引发咳嗽的加重因素。EP1 和 EP3 可能为咳嗽变异性哮喘提供新的治疗靶点。
