Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge

Abstract

Repeated low-dose allergen inhalation challenge mimics natural allergen exposure, providing a model for early mechanisms in the triggering of asthma. The current authors performed a controlled study to evaluate the time course of changes in exhaled nitric oxide fraction (Fe,NO) and urinary biomarkers of airway inflammation.Eight subjects with mild allergic asthma completed two 7-day repeated low-dose challenge periods, with diluent and allergen, respectively. Subjects were symptom free at inclusion and were investigated when not exposed to specific allergen. Pulmonary function and symptoms were followed, and Fe,NO and urinary mediators were correlated to changes in airway responsiveness to histamine and adenosine.Despite no change in pulmonary function (forced expiratory volume in one second mean¡SEM fall 0.3¡0.7 versus 0.6¡1.0%, for diluent and allergen, respectively) and no asthma symptoms, repeated allergen exposure, in contrast to diluent, caused significant increases in histamine responsiveness (2.3 doubling doses), an early and gradual increase in Fe,NO (up to a doubling from baseline) and a small increase in the mast cell marker 9a11b-prostaglandin F 2 after adenosine challenge.In conclusion, serial measurements of exhaled nitric oxide fraction have the potential to provide a very sensitive strategy for early detection of emerging airway inflammation and subsequent changes in airway hyperresponsiveness to histamine.

High‐ and low‐dose allergen challenges in asthmatic patients using inhaled corticosteroids

“…In previous repeated low-dose allergen challenge studies, ICS-naïve asthmatics demonstrated small reductions in FEV1 immediately after allergen exposure (ranging from 6.50 to 9.2%) without any significant effect on FEV1 measured the next morning [16][17][18][25][26][27][28][29]; this is similar to our findings. However, these previous studies also demonstrated increased airway inflammation; FeNO, sputum measurements of eosinophils and sputum Th2 mediators increased after low-dose challenge [18,27,28].…”

Effect of formoterol with or without budesonide in repeated low-dose allergen challenge

“…The exquisite sensitivity of FeNO measurements as a surrogate marker of the allergen-induced airway inflammation was particularly evident ( fig. 3) [17,20]. Conversely, there was no significant deterioration in morning FEV1, patient-recorded b 2 -agonist usage or evening lung function measurements at home.…”

“…In this challenge setting, patients with allergic asthma inhale fixed doses of allergen that are titrated to cause minimal bronchoconstriction and administered once daily on between four and 10 consecutive weekdays [17,18]. The procedure generates increased airway hyperresponsiveness to direct bronchoconstrictors and elevations in exhaled nitric oxide fraction (FeNO) and in inflammatory markers in sputum [17,18].…”

“…Repeated low-dose allergen inhalation challenge has been introduced as a method to mimic and standardise natural exposure to environmental allergens [16,17]. In this challenge setting, patients with allergic asthma inhale fixed doses of allergen that are titrated to cause minimal bronchoconstriction and administered once daily on between four and 10 consecutive weekdays [17,18].…”

Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models

“…However, even though mucosal thickening has smaller effects on airway resistance than on airway responsiveness [35], allergen-induced AHR persists after airway calibre has fully returned to baseline [36]. Moreover, AHR develops after challenge with low subclinical doses of allergen without significant change in pulmonary function [37,38]. Therefore, inflammation-induced alterations in the control of airway smooth muscle function are likely to be of major importance.…”