Alterations of the arginine metabolome in asthma.

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.

Signal transduction and oxidative processes in sinonasal polyposis.

BACKGROUND: Nasal polyposis is characterized by impaired regulation of nasal tissue growth and is associated with chronic inflammation, sinus infections, and low levels of nitric oxide (NO). Based on its critical role in mediating cell growth and antimicrobial function, decrease of NO levels has been implicated in the pathogenesis of nasal polyposis. OBJECTIVE: We sought to evaluate mechanisms for the low NO level in polyposis, including factors regulating NO synthase (NOS) expression and activity and NO consumptive processes in nasal epithelial cells and nasal lavage fluid. METHODS: Eighteen patients with nasal polyposis and 8 healthy control subjects were studied. Nasal brushings, nasal lavage fluid, and nasal biopsy specimens were collected and analyzed. RESULTS: NO metabolite levels (nitrite and nitrate) in nasal lavage fluid from patients with polyps were less than those in control subjects, but activation of signal transduction and inducer of transcription 1, which regulates inducible NOS gene expression and protein expression, was present at higher levels in polyp than in healthy control tissue. Levels of arginine, methylarginine, and endogenous NOS inhibitors were similar between polyp and control tissue. In contrast, superoxide dismutase activity of polyp tissues was lower than that seen in control tissue and associated with increased nitrotyrosine, a biomarker of oxidant consumptive products of NO. CONCLUSION: Taken together, these data suggest that the nasal polyp environment is characterized by abnormalities in NO metabolism that might predispose to altered regulation of tissue growth and infection. CLINICAL IMPLICATIONS: Identification of NO metabolic abnormalities might lead to novel treatments for sinonasal polyposis targeted against the pathways identified within this study.