Original Articles: Mechanisms of Allergy
Allergen-induced impairment of bronchoprotective nitric oxide synthesis in asthma,☆☆

https://doi.org/10.1067/mai.2001.116572Get rights and content

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 NG-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 (PD20BK) 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 (PD20BK, 70.8 nmol [range, 6.3-331] and 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 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 (Rs = –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. (J Allergy Clin Immunol 2001;108:198-204.)

Section snippets

Subjects

Ten nonsmoking, house dust mite–atopic individuals with clinically stable asthma participated in the study (Table I).

. Characteristics of participants

Patient no.SexAge (y)Atopic status*FVC (% predicted)†FEV1 (% predicted)†PC20FEV1 Histamine (mg/mL)‡
 1F205108900.61
 2F20495940.29
 3M213100810.74
 4M24698871.77
 5M264112921.0
 6F2141091031.33
 7M205102970.36
 8M19493964.23
 9F264961001.94
10F2431071043.34
*As determined by the number of wheal responses to 10 common allergen extracts (Vivodiagnost, ALK, Benelux).

The stability of asthma between the challenge days

Baseline FEV1 was not different between the diluent/allergen days (mean ± SEM): 3.83 ± 0.17 L (period 1), 3.78 ± 0.15 L (period 2), 3.83 ± 0.18 L (period 3), respectively (MANOVA, P = .42). Baseline FEV1 did not change significantly between the BK challenge days and was not affected by placebo or L-NMMA pretreatment (Table IV).

. FEV1 values (L) at baseline and after placebo/L-NMMA pretreatment on all bradykinin days of each study period

Empty CellPeriod 1Period 2Period 3
Day 3Day 10Day 3Day 10Day 3Day 10

Discussion

The present study shows that increased AHR to BK, induced by allergen exposure in asthma, is due to impaired production of bronchoprotective NO, a phenomenon that is associated with downregulation of ecNOS and upregulation of iNOS within the airway epithelium. These findings underscore the relevance of bronchoprotection by endogenous NO to limit AHR in asthma and warrant the development of treatment strategies to restore ecNOS activity during asthma exacerbations.

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References (45)

  • National Heart, Lung and Blood Institute

    Expert panel report 2. Guidelines for the diagnosis and management of asthma

    (1997)
  • PM O’Byrne et al.

    Late asthmatic responses

    Am Rev Respir Dis

    (1987)
  • DW Cockcroft et al.

    Allergen-induced increase in non-allergic bronchial reactivity

    Clin Allergy

    (1977)
  • AR Berman et al.

    Allergen-induced hyperresponsiveness to bradykinin is more pronounced than that to methacholine

    J Appl Physiol

    (1995)
  • AM Bentley et al.

    Human late asthmatic reactions

    Clin Exp Allergy

    (1997)
  • JK Sont et al.

    Enhanced expression of neutral endopeptidase (NEP) in airway epithelium in biopsies from steroid- versus non-steroid treated patients with atopic asthma

    Am J Respir Cell Mol Biol

    (1997)
  • M Figini et al.

    Evidence that epithelium-derived relaxing factor released by bradykinin in the guinea-pig trachea is nitric oxide

    Am J Respir Crit Care Med

    (1996)
  • J De Boer et al.

    Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study

    Br J Pharmacol

    (1996)
  • S Mehta et al.

    Endogenous nitric oxide and allergic bronchial hyperresponsiveness in guinea pigs

    Am J Physiol

    (1997)
  • M Schuiling et al.

    Role of nitric oxide in the development and partial reversal of allergen-induced airway hyperreactivity in conscious, unrestrained guinea-pigs

    Br J Pharmacol

    (1998)
  • H Meurs et al.

    Deficiency of nitric oxide in polycation-induced airway hyperreactivity

    Br J Pharmacol

    (1999)
  • WM Zapol et al.

    Nitric oxide and the lung

    (1997)
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    Supported by a Research Fellowship of the European Respiratory Society and by the Netherlands Asthma Foundation (grant 96.10).

    ☆☆

    Reprint requests: P. J. Sterk, MD, PhD, Department of Pulmonology, Lung Function Lab, C2-P, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, NL-2300 RC Leiden, The Netherlands. ([email protected] )

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