Elevated Exhaled Nitric Oxide in Allergen-Provoked Asthma Is Associated with Airway Epithelial iNOS

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.

Prenatal Particulate Air Pollution and Asthma Onset in Urban Children. Identifying Sensitive Windows and Sex Differences

“…Specifically, the airway epithelium may be a major source of IL-25, which regulates immune-mediated inflammatory airway diseases and the response to infections, and IL-33 and thymic stromal lymphopoietin, which also influence asthma development (47). Moreover, recent studies have found that epithelial barrier, epithelial mesenchymal transition, and mesenchymal phenotype are associated with lung function and allergic pulmonary diseases over the life course (47)(48)(49)(50). Factors involved in airway epithelial function and migration have been increasingly implicated in the links between PM, impaired lung growth, and asthma risk (51,52).…”

Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies

“…4 In the vascular system, the excessive amount of NO produced by iNOS is associated with decreased function of eNOS and subsequent impairment of both vasoconstriction and endothelium-dependent vasorelaxation. 6,7 Furthermore, the iNOSdependent detrimental overproduction of NO and related species such as peroxynitrites are implicated also in pathophysiological conditions such as asthma, 8 hypertension, 9 inflammatory bowel disease, 10 and cancer. 11,12 Selective inhibition of iNOS could therefore represent a feasible therapeutic strategy to treat the aforementioned and other conditions, and intense efforts to identify selective iNOS inhibitors have been carried out.…”

Predictive value of exhaled nitric oxide in healthy infants for asthma at school age

“…Given that environmental factors are known to induce NOS activity and modify FeNO [6,7,11,12], we hypothesised that FeNO measured after birth, and before relevant exposure to these factors, is not associated with asthma at school age.…”

“…In model 2, environmental factors (e.g. infections or air pollution) are needed to induce iNOS [6,7,11], which then results in elevated FeNO. In this hypothesis, we would expect no association between FeNO at birth (measured before environmental exposures) and school-age outcomes.…”

“…The interpretation of FeNO, its predictive value and its modifiers are age dependent [4,5,7,[9][10][11]. Postnatal FeNO metabolism seems to be modified by various environmental factors.…”