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.

Public Health Relevance

Asthma is a progressive inflammatory airways disease that leads to structural airway changes and debilitating symptoms in many severely affected adults. This clinical study has the potential to improve the care of adult severe asthmatics and to further our understanding of the mechanisms of L-arginine metabolism and nitric oxide biology in the lung. If we demonstrate that L-arginine supplementation can decrease asthma attacks in a subset of severe asthmatics, it will have great implications for future research as well as for the daily lives of patients with asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Freemer, Michelle M
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University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
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Bratt, Jennifer M; Chang, Kevin Y; Rabowsky, Michelle et al. (2018) Farnesyltransferase Inhibition Exacerbates Eosinophilic Inflammation and Airway Hyperreactivity in Mice with Experimental Asthma: The Complex Roles of Ras GTPase and Farnesylpyrophosphate in Type 2 Allergic Inflammation. J Immunol 200:3840-3856
Nguyen, Dan-Vinh; Linderholm, Angela; Haczku, Angela et al. (2017) Glucagon-like peptide 1: A potential anti-inflammatory pathway in obesity-related asthma. Pharmacol Ther 180:139-143
Zeki, Amir A; Bratt, Jennifer M; Chang, Kevin Y et al. (2015) Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung-targeted approach to deliver statins. Physiol Rep 3:
Yang, Jun; Bratt, Jennifer; Franzi, Lisa et al. (2015) Soluble epoxide hydrolase inhibitor attenuates inflammation and airway hyperresponsiveness in mice. Am J Respir Cell Mol Biol 52:46-55
Roodgar, Morteza; Ross, Cody T; Kenyon, Nicholas J et al. (2015) Inducible nitric oxide synthase (iNOS) regulatory region variation in non-human primates. Infect Genet Evol 31:236-44
Linderholm, Angela L; Bratt, Jennifer M; Schuster, Gertrud U et al. (2014) Novel therapeutic strategies for adult obese asthmatics. Immunol Allergy Clin North Am 34:809-23
Schuster, Gertrud U; Bratt, Jennifer M; Jiang, Xiaowen et al. (2014) Dietary long-chain omega-3 fatty acids do not diminish eosinophilic pulmonary inflammation in mice. Am J Respir Cell Mol Biol 50:626-36
Zeki, Amir A; Oldham, Justin; Wilson, Machelle et al. (2013) Statin use and asthma control in patients with severe asthma. BMJ Open 3:
Schivo, Michael; Seichter, Felicia; Aksenov, Alexander A et al. (2013) A mobile instrumentation platform to distinguish airway disorders. J Breath Res 7:017113
Kenyon, Nicholas J; Bratt, Jennifer M; Lee, Joyce et al. (2013) Self-assembling nanoparticles containing dexamethasone as a novel therapy in allergic airways inflammation. PLoS One 8:e77730

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