L-arginine as a therapy in severe asthma

描述(由申请人提供)：哮喘是一种进行性炎症性呼吸道疾病，在许多严重影响的成年人中会导致呼吸道结构改变和衰弱症状。我们需要新的治疗药物，既负担得起，又能减少对类固醇的依赖，能提高生活质量。这一临床和机制研究有可能影响部分成人重症哮喘患者的治疗，并进一步加深我们对哮喘患者呼吸道中L-精氨酸代谢和NO生物学机制的理解。我们将在标准药物治疗未得到很好控制的受试者中进行临床试验；这一策略将解决L-精氨酸对接受标准护理药物治疗的患者是否有效。在使用动物模型进行的研究中，我们和其他人已经证明，通过补充L精氨酸或抑制精氨酸酶来增加NO水平的干预措施，可以减少过敏性呼吸道炎症和高反应性--哮喘的两个特征。总体而言，我们假设，成人重症哮喘患者中的一部分“有反应”的患者将从补充L-精氨酸治疗中获得临床益处，这些患者的呼吸道上皮细胞中呼出的NO浓度将低于“无反应”患者(20 Ppb)，而NOS2/Arg1的mRNA和蛋白质比例高于“无反应患者”。我们的目标是：1)检验呼气NO浓度<20 ppb的未控制的成人重症哮喘患者在使用L精氨酸治疗3个月后哮喘恶化程度比使用FeNO&GT；25的患者更少的假设；2)确定L精氨酸影响重症哮喘患者原代呼吸道上皮细胞培养中一氧化氮合酶和精氨酸酶调节的机制，以及3)测试吸入L精氨酸纳米颗粒制剂将减轻呼吸道炎症、气道高反应性和气道纤维化的假设，剂量低于全身应用L精氨酸的患者。我们研究的主要影响将是确定将受益于补充L-精氨酸治疗的成人重度哮喘队列。我们的最终目标是开发新的治疗药物来更好地治疗成人重症哮喘患者。

DESCRIPTION (provided by applicant): Asthma is a progressive inflammatory airways disease that leads to structural airway changes and debilitating symptoms in many severely affected adults. We need novel therapeutic agents that are affordable, can decrease the reliance on steroids, and can improve quality of life. This clinical and mechanistic study has the potential to impact treatment of a subset of adult severe asthmatics and to further our understanding of the mechanisms of L-arginine metabolism and NO biology in the airways of asthmatics. We will pursue a clinical trial in subjects not well controlled on standard drug therapy; this strategy will address whether L-arginine is efficacious in patients receiving standard of care medications. In studies using animal models, we and others have shown that interventions that augment NO levels, through either supplementation of L-arginine or inhibition of arginase, decrease allergic airway inflammation and hyperresponsiveness-the two hallmarks of asthma. Overall, we hypothesize that a "responder" subset of adult severe asthma patients will derive clinical benefit from supplemental L-arginine therapy and that these patients will have a lower exhaled NO concentrations (<20 ppb) and a higher NOS2/Arg1 mRNA and protein ratio in their airway epithelial cells than "non-responders." We aim to: 1) test the hypothesis that uncontrolled, adult severe asthma patients with exhaled breath NO concentrations <20 ppb will have fewer asthma exacerbations over 3 months when treated with L-arginine compared to patients with FeNO > 25, 2) determine the mechanisms by which L-arginine affects the regulation of NOS and arginase enzymes in primary airway epithelial cell cultures from severe asthmatic subjects, and 3) test the hypothesis that inhaled nanoparticle carrier formulations of L-arginine will decrease airway inflammation, airway hyperresponsiveness, and airway fibrosis at lower doses than systemically administered L-arginine. The major impact of our study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy. Our ultimate goal is to develop novel therapeutic agents to treat adult severe asthma patients better.