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Post-allergen challenge inhibition of poly(ADP-ribose) polymerase harbors therapeutic potential for treatment of allergic airway inflammation

机译：过敏原激发后的聚（ADP-核糖）聚合酶抑制作用具有治疗过敏性气道炎症的治疗潜力

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Background: Identifying therapeutic drugs that block the release or effects of T-helper type 2 (Th2) cytokines after allergen exposure is an important goal for the treatment of allergic inflammatory diseases including asthma. We recently showed, using a murine model of allergic airway inflammation, that poly(ADP-ribose) polymerase (PARP) plays an important role in the pathogenesis of asthma-related lung inflammation. PARP inhibition, by single injection of a novel inhibitor, thieno[2,3-c]isoquinolin-5-one (TIQ-A), before ovalbumin (OVA) challenge, prevented airway eosinophilia in C57BL/6 mice with concomitant suppression of Th2 cytokine production and mucus secretion. Objective: To evaluate the efficacy of the drug when it is given after OVA challenge for its possible therapeutic potential. Methods: This study was conducted using a murine model of allergic airway inflammation. Results: A single injection of TIQ-A (6 mg/kg) one or 6 h post-allergen challenge conferred similar reduction in OVA challenge-induced eosinophilia. More significantly, post-allergen challenge administration of the drug exerted even better suppression on the production of IL-4, IL-5, IL-13, and IgE and prevented airway hyperresponsiveness to inhaled-methacholine. The significant decrease in IL-13 was accompanied by a complete absence of airways mucus production indicating a potential protection against allergen-induced airway remodelling. Conclusion: The coincidence of the inflammation trigger and the time of drug administration appear to be important for the drug's more pronounced protection. The observed time window for efficacy, 1 or 6 h after allergen challenge may be of great clinical interest. These findings may provide a novel therapeutic strategy for the treatment of allergic airway inflammation, including asthma.
机译：背景：确定在暴露于过敏原后能阻断2型T辅助细胞因子（Th2）释放或作用的治疗药物，是治疗包括哮喘在内的过敏性炎症疾病的重要目标。我们最近使用变应性气道炎症的鼠模型显示，聚（ADP-核糖）聚合酶（PARP）在哮喘相关的肺部炎症的发病机理中起着重要的作用。在卵清蛋白（OVA）攻击前，通过单次注射新型抑制剂硫代[2,3-c]异喹啉-5-酮（TIQ-A）抑制PARP可以预防C57BL / 6小鼠气道嗜酸性粒细胞增多，并同时抑制Th2细胞因子产生和粘液分泌。目的：评估在OVA攻击后给予该药物的疗效，以评估其有效性。方法：本研究是使用鼠过敏性气道炎症模型进行的。结果：在过敏原激发后1或6小时单次注射TIQ-A（6 mg / kg）可使OVA激发诱导的嗜酸性粒细胞减少。更重要的是，过敏原激发后给药对IL-4，IL-5，IL-13和IgE的产生产生了更好的抑制作用，并防止了气道对吸入美沙胆碱的过敏反应。 IL-13的显着降低伴有气道粘液的完全缺乏，表明对变应原诱导的气道重塑具有潜在的保护作用。结论：炎症触发的同时发生和给药时间似乎对于更明显地保护药物很重要。在过敏原激发后1或6 h观察到的疗效时间窗可能具有重大的临床意义。这些发现可能为治疗过敏性气道炎症（包括哮喘）提供一种新颖的治疗策略。

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