Abstract
BackgroundFractional exhaled nitric oxide is elevated in allergen-provoked asthma. The cellular and molecular source of the elevated fractional exhaled nitric oxide is, however, uncertain.ObjectiveTo investigate whether fractional exhaled nitric oxide is associated with increased airway epithelial inducible nitric oxide synthase (iNOS) in allergen-provoked asthma.MethodsFractional exhaled nitric oxide was measured in healthy controls (n = 14) and allergic asthmatics (n = 12), before and after bronchial provocation to birch pollen out of season. Bronchoscopy was performed before and 24 hours after allergen provocation. Bronchial biopsies and brush biopsies were processed for nitric oxide synthase activity staining with nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), iNOS immunostaining, or gene expression analysis of iNOS by real-time PCR. NADPH-d and iNOS staining were quantified using automated morphometric analysis.ResultsFractional exhaled nitric oxide and expression of iNOS mRNA were significantly higher in un-provoked asthmatics, compared to healthy controls. Allergic asthmatics exhibited a significant elevation of fractional exhaled nitric oxide after allergen provocation, as well as an accumulation of airway eosinophils. Moreover, nitric oxide synthase activity and expression of iNOS was significantly increased in the bronchial epithelium of asthmatics following allergen provocation. Fractional exhaled nitric oxide correlated with eosinophils and iNOS expression.ConclusionHigher fractional exhaled nitric oxide concentration among asthmatics is associated with elevated iNOS mRNA in the bronchial epithelium. Furthermore, our data demonstrates for the first time increased expression and activity of iNOS in the bronchial epithelium after allergen provocation, and thus provide a mechanistic explanation for elevated fractional exhaled nitric oxide in allergen-provoked asthma.
Highlights
Allergic asthma is characterized by airway hyperreactivity and variable airflow obstruction caused by an abnormal inflammatory response to foreign antigens, and presence of allergen-specific serum IgE
Higher fractional exhaled nitric oxide concentration among asthmatics is associated with elevated inducible nitric oxide synthase (iNOS) mRNA in the bronchial epithelium
Our data demonstrates for the first time increased expression and activity of iNOS in the bronchial epithelium after allergen provocation, and provide a mechanistic explanation for elevated fractional exhaled nitric oxide in allergen-provoked asthma
Summary
Allergic asthma is characterized by airway hyperreactivity and variable airflow obstruction caused by an abnormal inflammatory response to foreign antigens, and presence of allergen-specific serum IgE. Enhanced knowledge of the mechanisms contributing to allergic asthma and improved disease monitoring is key to prevent increasing morbidity and mortality, and to limit rising health care costs. Fractional exhaled nitric oxide (FENO) is a validated marker for airway inflammation [2,3,4] that correlates with airway eosinophilia [5], suggesting a particular relevance for asthma management. The activity of inducible nitric oxide synthase (iNOS/NOS2) in the airway epithelium has been suggested to be the most important determining factor for the concentration of FENO in stable asthma [8,9,10]. We hypothesized that elevated FENO in allergen-induced asthma is associated with increased expression of iNOS. Fractional exhaled nitric oxide is elevated in allergen-provoked asthma. The cellular and molecular source of the elevated fractional exhaled nitric oxide is, uncertain
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