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.

摘要