Allergen-induced impairment of bronchoprotective nitric oxide synthesis inasthma

Background: Eudogenous nitric oxide protects against airway hyperresponsive ness (AHR) to bradykinin in mild asthma, whereas AHR to bradykinin is enhan ced by inhaled allergens. Objective: Hypothesizing that allergen exposure impairs bronchoprotective n itric oxide within the airways, we studied the effect of the inhaled nitric ox:ide synthase. (NOS) inhibitor N-G-monomethyl-L-arginine, (L-NMMA) on AH R to bradykinin before and after allergen challenge in 10 subjects with ato pic asthma. Methods: The study consisted or 3 periods (1 diluent and 2 allergen challen ges). AHR to bradylkinin (PD20BK) was examined before and 48 hours after al lergen challenge, both after double-blinded pretreatment with L-NMMA or pla cebo. The accompanying expression of the various NOS isoforms (ecNOS, nNOS, and iNOS) was examined by means of immunohistochemistry in bronchial biops ies obtained after diluent and allergen challenge. Results: After placebo, AHR to BK worsened after allergen challenge in comp arison with before allergen challenge (PD20BK, 70.8 nmol [range, 6.3-331] a nd 257 nmol [35.5-2041], respectively; P=.0004). After L-NMMA, preallergen and postallergen PD20BK values (50.1 nmol [1.8-200] vs 52.5 nmol [6.9-204]; P =.88) were similarly reduced (P <.01) and not different from the postpla cebo/postallergen value (P>.05). After allergen challenge, the intensity of staining in bronchial epithelium decreased for ecNOS (P=.03) and increased for iNOS (P=.009). These changes in immunostaining were correlated with th e accompanying worsening in AHR to BK (R-s = -0.66 and 0.71; P<.04). Conclusions: These data indicate that allergen exposure in asthma induces i ncreased airway hyperresponsiveness to bradykinin through impaired release of bronchoprotective nitric oxide associated with downregulation of ecNOS. This suggests that new therapeutic strategies towards restoring the balance among the NOS isoforms during asthma exacerbations are warranted.