SANDIA: Supplementing L-citrulline to overweight late Asthma oNset phenotypes to increase airway L-arginine/ADMA ratio and Improve Asthma control

SANDIA：补充 L-瓜氨酸以治疗晚期哮喘发作表型超重，以增加气道 L-精氨酸/ADMA 比率并改善哮喘控制

• 批准号: 10226815
• 负责人: Fernando Holguin
• 金额: $ 70.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226815
• 关键词: 3-nitrotyrosine; Adult; Affect; Air; Anabolism; Arginine; Asthma; Bioenergetics; Biological Availability; Biological Markers; Blinded; Blood; Body mass index; Bronchial Hyperreactivity; Bronchoconstriction; Bronchodilator Agents; Bronchoscopy; Brush Cell; Cell Culture Techniques; Childhood; Citrulline; Clinical; Clinical Trials; Cross-Over Studies; Data; Disease; Double-Blind Method; Enzymes; Epithelial; Epithelial Cells; Exhalation; Female; Free Radical Formation; Frequencies; Generations; Human; Impairment; Inflammation; Intervention; Irrigation; Liquid substance; Measures; Mediating; Metabolic Pathway; Metabolism; Mitochondria; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Synthase; Obesity; Overweight; Oxidative Stress; Oxygen; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Placebos; Plasma; Population; Precision therapeutics; Production; Pulmonary Function Test/Forced Expiratory Volume 1; Quality of life; Reactive Oxygen Species; Regulation; Research; Research Design; Respiratory Signs and Symptoms; S-Nitrosoglutathione; Sputum; Supplementation; Symptoms; Testing; Translational Research; United States; airway epithelium; airway inflammation; allergic airway inflammation; arginase; asthmatic; asthmatic airway; asthmatic patient; comorbidity; conventional therapy; density; falls; improved; multidisciplinary; nitrosative stress; novel; novel therapeutics; obese patients; obesity treatment; open label; primary outcome; pulmonary function; secondary analysis; secondary outcome; tool

ABSTRACT Obesity affects approximately 40% of adult asthmatics in the U.S. Obese patients who develop asthma after childhood (Late onset), can be highly symptomatic and poorly controlled despite having lower exhaled nitric oxide (FeNO) levels. This type of late onset asthma is a frequent phenotype encountered in adults, particularly among obese females. Because these asthmatics have predominantly non-T2 type airway inflammation, they often fail to respond to conventional therapy and are burdened by uncontrolled symptoms imploring the identification of novel precision therapeutic approaches for this predominant asthma phenotype. Several key clinical observations have led to our identification of a potential mechanistic pathway in late onset obese asthmatics that can account for their reduced FeNO and worsening respiratory symptoms. Among these subjects, increasing BMI associates with reduced bioavailability of NO, an important endogenous bronchodilator. The reduction of NO occurs through uncoupling of NO synthase (NOS), by accumulation of asymmetric di-methyl arginine (ADMA). This preferentially promotes reactive oxygen species (ROS) formation at the expense of NO production, which can also result in loss of S-nitrosoglutathione (GSNO), a potent endogenous bronchodilator, further promoting bronchoconstriction. In these asthmatics, lower plasma L-arginine/ADMA ratios, are associated with lower FeNO, reduced lung function and asthma related quality of life, as well as increased respiratory symptom frequency. Moreover, in primary human airway epithelial cells low L-arginine uncouples inducible NOS (iNOS), reducing NO bioavailability, and increasing ROS. L-arginine deficiency can also contribute to increased free radical formation and airway inflammation by impairing mitochondrial function. In our pilot studies, the administration of L-citrulline to patients with late onset asthma augments sputum L-arginine and the L- arginine/ADMA ratio, increasing FEV1 and FeNO, while improving asthma control. Further, in asthmatic airway epithelial cells, L-citrulline reverses ADMA-mediated NOS uncoupling and decreases nitrotyrosine formation. We hypothesize that L-citrulline supplementation is a safe, novel drug strategy to treat obese late onset asthma by restoring L-arginine/ADMA ratio, decreasing oxidative and nitrosative stress, and ultimately reducing bronchial hyperresponsiveness and improving asthma control. To test this hypothesis, we will treat late onset obese asthmatics with L-citrulline in a proof of concept (POC) study (Aim 1). Before and after blinded treatment, bronchoscopic lavage and epithelial brushing analyses will be performed in a subset of study participants to identify underlying mechanisms at the cellular (Aim 2) and subcellular levels (Aim 3). As current medications have limited efficacy in obese late onset asthma, new therapeutics are needed. This study allows us the unique opportunity to test a novel therapy for obese asthma and focus on a component that could also be relevant for non T2 phenotypes, which accounts for roughly half of the asthmatic population.

抽象的 在美国，大约 40% 的成人哮喘患者患有肥胖症。 儿童期（晚发），尽管呼出一氧化氮较低，但症状可能很严重且控制不佳 （FeNO）水平。这种类型的迟发性哮喘是成人中常见的表型，尤其是在成人中 肥胖女性。由于这些哮喘患者主要患有非 T2 型气道炎症，因此他们常常无法 对传统疗法有反应，并受到不受控制的症状的困扰，恳求识别新的治疗方法 针对这种主要哮喘表型的精准治疗方法。 几个关键的临床观察使我们识别出晚期潜在的机制途径 肥胖性哮喘患者的 FeNO 减少和呼吸道症状恶化是其发病原因。之中 在这些受试者中，BMI 的增加与 NO 的生物利用度降低相关，NO 是一种重要的内源性物质。 支气管扩张剂。 NO 的还原是通过 NO 合酶 (NOS) 的解偶联、通过积累 不对称二甲基精氨酸（ADMA）。这优先促进活性氧 (ROS) 的形成 NO 产生的代价，这也可能导致 S-亚硝基谷胱甘肽 (GSNO) 的损失，GSNO 是一种有效的内源性 支气管扩张剂，进一步促进支气管收缩。在这些哮喘患者中，血浆 L-精氨酸/ADMA 比率较低， 与较低的 FeNO、降低的肺功能和哮喘相关的生活质量以及增加的 呼吸道症状的频率。此外，在原代人气道上皮细胞中，低 L-精氨酸解偶联 诱导型一氧化氮合酶（iNOS），降低一氧化氮生物利用度，增加活性氧。 L-精氨酸缺乏也会导致 通过损害线粒体功能来增加自由基形成和气道炎症。在我们的试点研究中， 给晚发性哮喘患者服用 L-瓜氨酸可增加痰中 L-精氨酸和 L- 精氨酸/ADMA 比率，增加 FEV1 和 FeNO，同时改善哮喘控制。此外，在哮喘气道中 在上皮细胞中，L-瓜氨酸可逆转 ADMA 介导的 NOS 解偶联并减少硝基酪氨酸的形成。我们 假设 L-瓜氨酸补充剂是一种安全的新型药物策略，可通过以下方式治疗肥胖晚发性哮喘： 恢复 L-精氨酸/ADMA 比例，减少氧化和亚硝化应激，最终减少支气管炎 高反应性并改善哮喘控制。 为了验证这一假设，我们将在概念验证中用 L-瓜氨酸治疗迟发性肥胖哮喘患者 （POC）研究（目标 1）。盲法治疗前后、支气管镜灌洗和上皮刷洗分析 将在一部分研究参与者中进行，以确定细胞的潜在机制（目标 2）和 亚细胞水平（目标 3）。 由于目前的药物对肥胖晚发性哮喘的疗效有限，因此需要新的治疗方法。这 研究为我们提供了独特的机会来测试肥胖哮喘的新疗法，并重点关注以下成分： 也可能与非 T2 表型有关，非 T2 表型约占哮喘人群的一半。