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 肥胖会影响美国肥胖患者大约40％的成人哮喘患者 童年（晚发），尽管一氧化氮的呼气较低 （feno）水平。这种类型的晚期发病哮喘是成年人经常遇到的表型，尤其是在 肥胖女性。因为这些哮喘患者主要具有非T2型气道炎症，所以它们通常无法 对常规疗法做出反应，并因恳求新颖的鉴定而受到不受控制的症状负担 这种主要的哮喘表型的精确治疗方法。 几个关键的临床观察结果已导致我们对近来潜在机械途径的识别 发作肥胖的哮喘患者可以解释其减少的Feno和恶化呼吸道症状。之中 这些受试者增加了BMI与降低的生物利用度相关联，这是一个重要的内源性内源性的 支气管扩张剂。通过将NO合酶（NOS）解偶联而降低NO的减少，通过积累 非对称二甲基精氨酸（ADMA）。这优先促进活性氧（ROS）形成 没有生产的费用，这也可能导致S-硝基谷硫硫代（GSNO）的损失，这是一种有效的内源性的 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相关，肺功能降低和与生活相关的生活质量以及增加 呼吸道症状频率。此外，在原发性气道上皮细胞中 可诱导的NOS（iNOS），降低没有生物利用度，并增加ROS。 L-精氨酸缺乏也可以贡献 通过损害线粒体功能来增加自由基的形成和气道炎症。在我们的试点研究中 升发作哮喘哮喘肿瘤L-精氨酸和L- 精氨酸/ADMA比，增加FEV1和FENO，同时改善哮喘控制。此外，在哮喘气道中 上皮细胞L-citrulline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-西曲霉补充是一种安全的新型药物策略，可通过 恢复L-精氨酸/ADMA比，减少氧化和亚硝化应激，并最终降低支气管 反应性过高并改善哮喘控制。 为了检验这一假设，我们将用l-citrulline在概念证明中对待晚期肥胖哮喘患者 （POC）研究（目标1）。盲治疗前后，支气管镜灌洗和上皮刷分析 将在研究参与者的一部分中进行，以识别细胞的基本机制（AIM 2）和 亚细胞水平（AIM 3）。 由于目前的药物在肥胖的晚期哮喘中的疗效有限，因此需要新的治疗疗法。这 研究使我们有独特的机会来测试肥胖哮喘的新疗法，并专注于一个成分 也可能与非T2表型有关，该表型约占哮喘人群的一半。