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首页> 外文期刊>American Journal of Physiology >Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice
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Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice

机译：口服凝血酶抑制剂Dabigatran对小鼠反复宫螨螨施用诱导的过敏性肺炎症的影响

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摘要

Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P < 0.05) and decreased IL-4 levels (P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.
机译：哮喘是气道的慢性疾病;哮喘患者受到呼吸困难症状和支气管阻塞引起的喘息症状的阻碍。大多数哮喘患者患有由过敏原触发的慢性过敏性肺炎，如房屋粉尘（HDM）。肺隔室中的凝血活化目前被认为是过敏性肺炎症的特征，数据表明凝固蛋白酶进一步驱动炎症机制。在这里，我们测试了口腔凝血酶抑制剂Dabigatran的治疗是否衰减最近开发的HDM的鼠哮喘模型中的过敏性肺炎。在3 WK HDM气道曝光模型期间，将小鼠喂食Dabigatran（10mg / g）或安慰剂咸。 Dabigatran治疗导致人类试验中报告的Dabigatran水平对应的系统性凝血酶抑制活性。令人惊讶的是，Dabigatran没有导致通过凝血酶 - 抗凝血酶复合物和D-二聚体的水平测量的肺部抑制HDM诱发的凝血活化。重复的HDM给药导致嗜酸性粒细胞和中性粒细胞的流入肺部，气道粘液产生，以及T辅助2反应，如支气管肺泡IL-4和IL-5水平的上升和IgE和HDM的全身升高-igg1。 Dabigatran适度改善HDM诱导的肺病理学（P <0.05）并降低IL-4水平（P <0.01），不影响其他HDM诱导的反应。考虑到Dabigatran尽管有足够的血浆水平，但这些结果争论Dabigatran在哮喘患者中的临床评价。

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