Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.
Allergol Int. 2017 Sep;66S:S21-S26. doi: 10.1016/j.alit.2017.05.004. Epub 2017 Jun 21.
Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration.
A/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50-52) and poly I:C (phase 2: days 53-55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56.
Administration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models.
This is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target.
病毒感染是哮喘恶化最常见的诱因，但这一过程中涉及的关键分子尚未完全确定。虽然半胱氨酰白三烯（cysteinyl leukotrienes，cysLTs）被认为是关键介质，但它们的确切作用仍在很大程度上不清楚。为了研究 cysLTs 在病毒诱导的哮喘恶化中的作用，我们使用病毒双链 RNA 类似物聚肌胞苷酸（poly I:C）建立了一种小鼠模型，并分析了白三烯受体拮抗剂（leukotriene receptor antagonist，LTRA）给药的效果。
A/J 小鼠用卵清蛋白（ovalbumin，OVA）+明矾（days 0, 28, 42, and 49）免疫，然后用 OVA（第 1 阶段：days 50-52）和 poly I:C（第 2 阶段：days 53-55）进行鼻内挑战。在 poly I:C 挑战（第 2 阶段）中，在缓解模型中给予孟鲁司特，或在 OVA 和 poly I:C 挑战（第 1 和第 2 阶段）中，在控制模型中给予孟鲁司特。评估乙酰胆碱氯对气道的反应性，并在第 56 天进行支气管肺泡灌洗（bronchoalveolar lavage，BAL）。
将 poly I:C 给予 OVA 致敏和攻击的小鼠，增加了 BAL 液中嗜酸性粒细胞的数量和白细胞介素-13（IL-13）、白细胞介素-9（IL-9）、CCL3 和 CXCL1 的水平，并使气道反应性增加的趋势。孟鲁司特显著减轻了缓解和控制模型中 poly I:C 诱导的嗜酸性粒细胞数量增加、BAL 液中 IL-13、IL-9 和 CCL3 水平升高以及气道高反应性。
这是第一项报告表明，LTRA 从功能上抑制了病毒诱导的哮喘恶化模型的病理生理学，这表明 cysLTs 作为一种潜在的治疗靶点的重要性。
