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Alterations of the Arginine Metabolome in Asthma

¹ Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio; ² Pulmonary and Critical Care Medicine, MetroHealth Medical Center, Cleveland, Ohio; Departments of ³ Cell Biology, and ⁴ Pulmonary, Allergy and Critical Care Medicine, Cleveland Clinic, Cleveland, Ohio; ⁵ Wake Forest University, Winston-Salem, North Carolina; ⁶ University of Wisconsin, Madison, Wisconsin; ⁷ University of Texas, Galveston, Texas; ⁸ Washington University in St. Louis, St. Louis, Missouri; ⁹ Imperial College School of Medicine, London, United Kingdom; ¹⁰ National Jewish Medical and Research Center, Denver, Colorado; ¹¹ University of Virginia, Charlottesville, Virginia; ¹² Brigham and Women's Hospital, Boston, Massachusetts; ¹³ Emory University, Atlanta, Georgia; and ¹⁴ University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Serpil C. Erzurum, M.D., The Cleveland Clinic, 9500 Euclid Avenue, NC2-123, Cleveland, OH 44195. E-mail: erzurus{at}ccf.org

Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation.

Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity.

Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FE_NO), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated.

Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FE_NO and serum arginase activity. However, Arg bioavailability was positively associated with FE_NO only in healthy control subjects; Arg bioavailability was unrelated to FE_NO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma.

Conclusions: Unlike FE_NO, Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.

Key Words: asthma • arginine • arginase • nitric oxide • methylarginine

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Studies suggest that alterations in arginine (Arg) metabolic pathways, such as the arginases and nitric oxide (NO) synthases, play a role in asthma pathophysiology. What This Study Adds to the Field In this study, we show that quantitative assessment of metabolites critical to Arg and NO pathways are informative for determination of airflow abnormalities linked to remodeling in severe asthma.