L-CitrullineSupplementing L-citrulline to Overweight Late Asthma oNset Phenotypes

Patients with obese late onset (after childhood) asthma can have lower FeNO levels, yet be highly symptomatic and poorly responsive to inhaled steroids. This is a common asthma phenotype, particularly among females. This reduction of NO occurs through increased arginase activity and uncoupling of NO synthase (NOS), by accumulation of asymmetric di-methyl arginine (ADMA), which further lowers the L-arginine/ADMA ratio, preferentially promoting reactive oxygen species (ROS) formation and inflammation at the expense of NO. Indeed, in patients with obese late onset asthma, lower L-arginine/ADMA plasma ratios are associated with reduced FeNO, increased bronchial hyperreactivity, and greater asthma morbidity. In our pilot studies, the administration of L-citrulline, as an L-arginine donor, to patients with obese late onset asthma increased the L-arginine/ADMA ratio, FeNO levels, and improved asthma control and lung function. Therefore, the objectives of the protocol are to: a) determine the efficacy of L-citrulline, as an add-on treatment to improve the asthma control and lung function in obese late onset asthmatics; b) leverage the use of asthmatic and control cells to further understand obesity-related changes in epithelial airway NO metabolism, and how these changes relate to bronchoconstriction and lung function, c) determine airway epithelial changes in mitochondrial function and bioenergetics in obese late onset asthmatics and how these are modified by L-citrulline. To do this, 54 obese late onset asthmatics with suboptimal control will be blindly randomized, in a cross over study, comparing 15g/day of L-citrulline vs. placebo, in two 8-week treatment periods with a 6-week washout in between. The co-primary study outcomes are asthma control (ACQ, ACT) and FeNO, and secondary endpoints plasma L-arginine/ADMA, FEV1 and PC20 methacholine. Parallel to this study, a small study of 10 healthy obese controls will receive open label L-citrulline for 7 weeks to establish comparative reference values for the study aims. During the initial treatment phase, 50% of study participants will be randomly allocated to undergo pre and post L-citrulline treatment bronchoscopy to obtain BAL and airway epithelial cells. The research group proposing this study is highly experience in asthma clinical trials, implementation of cross over design studies, and in the use of research bronchoscopies.