Published ahead of print on July 17, 2008, doi:10.1164/rccm.200710-1542OC Am. J. Respir. Crit. Care Med., Volume 178, Number 7, October 2008, 673-681 A more recent version of this article appeared on October 1, 2008
Submitted on October 18, 2007 Alterations of the Arginine Metabolome in AsthmaAbigail Lara1,1 Departments of Pathobiology, The Lerner Research Institute, Cleveland, OH, USA, 2 Departments of Pathobiology, The Lerner Research Institute, Cleveland, OH, USA; Pulmonary and Critical Care Medicine, MetroHealth Medical Center, Cleveland, OH, USA, 3 Cell Biology, The Lerner Research Institute, Cleveland, OH, USA, 4 Departments of Pathobiology, The Lerner Research Institute, Cleveland, OH, USA; Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic, Cleveland, OH, USA; National Heart Lung Blood Institue Severe Asthma Research Program (SARP), Bethesda, MD, USA, 5 National Heart Lung Blood Institue Severe Asthma Research Program (SARP), Bethesda, MD, USA * To whom correspondence should be addressed. 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 bioavailability would be associated with airflow abnormalities and inflammation in asthmatics, and would be informative for asthma severity. Methods: Arginine bioavailability was assessed in severe and nonsevere asthmatics and healthy controls by determination of plasma arginine relative to its metabolic products ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including exhaled NO (FENO), IgE, skin test positivity to allergens, bronchoalveolar lavage (BAL) and blood eosinophils, were also evaluated. Results: Asthmatics had greater arginine bioavailability but also increased arginine catabolism compared to healthy controls, as evidenced by higher levels of FENO, and serum arginase activity. However, arginine bioavailability was positively associated with FENO, only in healthy controls; arginine bioavailability was unrelated to FENO, 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, arginine bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of arginine bioavailabilty predict airflow obstruction only in severe asthma. Conclusions: Unlike FENO, arginine bioavailability is not a surrogate measure of inflammation, however arginine bioavailability is strongly associated with airflow abnormalities in severe asthma. Key words: asthma, arginine, arginase, nitric oxide, methylarginine
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