Background. Quinoline-3-carboxamides have been used to treat autoimmune/inflammatory diseases in humans because they inhibit the functions of S100 calcium-binding protein A9 (S100A9), which participates in the development of neutrophilic inflammation in asthmatics and in an animal model of neutrophilic asthma. However, the therapeutic effects of these chemicals have not been evaluated in asthma. The purpose of this study was to evaluate the effect of paquinimod, one of the quinoline-3-carboxamides, on a murine model of neutrophilic asthma. Methods. Paquinimod was orally administered to 6-week-old C57BL/6 mice sensitized and challenged with ovalbumin (OVA)/complete Freund’s adjuvant (CFA) and OVA. Lung inflammation and remodeling were evaluated using bronchoalveolar lavage (BAL) and histologic findings including goblet cell count. S100A9, caspase-1, IL-1β, MPO, IL-17, IFN-γ, and TNF-α were measured in lung lysates using western blotting. Results. Paquinimod restored the enhancement of airway resistance and the increases in numbers of neutrophils and macrophages of BAL fluids and those of goblet cells in OVA/CFA mice toward the levels of sham-treated mice in a dose-dependent manner (0.1, 1, 10, and 25 mg/kg/day, p.o.). Concomitantly, p20 activated caspase-1, IL-1β, IL-17, TNF-α, and IFN-γ levels were markedly attenuated. Conclusion. These data indicate that paquinimod effectively inhibits neutrophilic inflammation and remodeling in the murine model of neutrophilic asthma, possibly via downregulation of IL-17, IFN-γ, and IL-1β.

中文翻译：

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帕喹莫德对卵清蛋白与完全弗氏佐剂诱导的中性粒细胞性哮喘小鼠模型的抑制作用

背景。喹啉-3-甲酰胺已被用于治疗人类自身免疫/炎症性疾病，因为它们抑制 S100 钙结合蛋白 A9 (S100A9) 的功能，该蛋白参与哮喘患者中性粒细胞炎症和中性粒细胞哮喘动物模型的发展. 然而，这些化学物质的治疗效果尚未在哮喘中进行评估。本研究的目的是评估一种喹啉-3-羧酰胺类药物帕喹莫德对中性粒细胞哮喘小鼠模型的影响。方法. 将帕喹莫德口服给予用卵清蛋白 (OVA)/完全弗氏佐剂 (CFA) 和 OVA 致敏和攻击的 6 周龄 C57BL/6 小鼠。使用支气管肺泡灌洗液 (BAL) 和包括杯状细胞计数在内的组织学发现评估肺部炎症和重塑。使用蛋白质印迹在肺裂解物中测量S100A9、caspase-1、IL-1 β、MPO、IL-17、IFN- γ和 TNF - α 。结果。Paquinimod 以剂量依赖的方式使 OVA/CFA 小鼠气道阻力的增强以及 BAL 液和杯状细胞的中性粒细胞和巨噬细胞数量的增加恢复到假治疗小鼠的水平 (0.1, 1, 10,和 25 mg/kg/天，口服）。同时，p20 激活 caspase-1、IL-1 β、IL-17、TNF- α和 IFN- γ水平显着降低。结论。这些数据表明，帕喹莫德有效抑制中性粒细胞哮喘小鼠模型中的中性粒细胞炎症和重塑，可能通过下调 IL-17、IFN- γ和 IL- 1β。