title: Allergen-induced impairment of bronchoprotective nitric oxide synthesis in asthma.
abstract: BACKGROUND
  Endogenous nitric oxide protects against airway hyperresponsiveness (AHR) to bradykinin in mild asthma, whereas AHR to bradykinin is enhanced by inhaled allergens.
  
  
  OBJECTIVE
  Hypothesizing that allergen exposure impairs bronchoprotective nitric oxide within the airways, we studied the effect of the inhaled nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on AHR to bradykinin before and after allergen challenge in 10 subjects with atopic asthma.
  
  
  METHODS
  The study consisted of 3 periods (1 diluent and 2 allergen challenges). AHR to bradykinin (PD(20)BK) was examined before and 48 hours after allergen challenge, both after double-blinded pretreatment with L-NMMA or placebo. The accompanying expression of the various NOS isoforms (ecNOS, nNOS, and iNOS) was examined by means of immunohistochemistry in bronchial biopsies obtained after diluent and allergen challenge.
  
  
  RESULTS
  After placebo, AHR to BK worsened after allergen challenge in comparison with before allergen challenge (PD(20)BK, 70.8 nmol [range, 6.3-331] and 257 nmol [35.5-2041], respectively; P =.0004). After L-NMMA, preallergen and postallergen PD(20)BK 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 postplacebo/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 the 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 increased 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.
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, The Netherlands.
authors.forename: F L
authors.initials: FL
authors.lastname: Ricciardolo
authors.forename: M C
authors.initials: MC
authors.lastname: Timmers
authors.forename: P
authors.initials: P
authors.lastname: Geppetti
authors.forename: A
authors.initials: A
authors.lastname: van Schadewijk
authors.forename: J J
authors.initials: JJ
authors.lastname: Brahim
authors.forename: J K
authors.initials: JK
authors.lastname: Sont
authors.forename: H W
authors.initials: HW
authors.lastname: de Gouw
authors.forename: P S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: J H
authors.initials: JH
authors.lastname: van Krieken
authors.forename: P J
authors.initials: PJ
authors.lastname: Sterk
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology*; D001249:Asthma / Q000276:immunology*; D001920:Bradykinin / Q000276:immunology*; D001980:Bronchi / Q000276:immunology*; D005260:Female; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000302:isolation & purification; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000302:isolation & purification; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000485:Allergens; D007527:Isoenzymes; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001920:Bradykinin