Mechanisms of asthma and allergic inflammation
Oxidative stress and genetic and epidemiologic determinants of oxidant injury in childhood asthma

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Background

The factors contributing to the oxidant/antioxidant imbalance in asthma are incompletely understood.

Objective

To determine the factors associated with oxidative stress including asthma severity and the genotype of the antioxidant enzymes.

Methods

A total of 196 children with mild asthma, 116 children with moderate-severe asthma, and 2 healthy control groups (187 and 68 children) were included in the study. Plasma levels of malondialdehyde were measured as the indicator of oxidative stress, and reduced glutathione levels as the indicator of antioxidant defense. Children were genotyped for null variants of glutathione S transferase (GST) T1 and GSTM1, and ile105val variant of GSTP1. Risk factors were analyzed with multivariate logistic regression.

Results

Systemic levels of malondialdehyde increased and reduced glutathione levels decreased significantly from healthy controls to patients with mild asthma and then to patients with moderate-severe asthma (P < .001 for each). Multivariate logistic regression identified asthma and asthma severity as independent factors associated with oxidative stress (odds ratio between 17 and 56; P < .001). Children with asthma with GSTP1 val/val genotype had higher malondialdehyde and lower glutathione levels compared with other genotypes (P = .023 and P = .014, respectively). GSTP1 val/val genotype was independently associated with asthma severity (odds ratio, 4.210; 95% CI, 1.581-11.214; P = .004).

Conclusion

Our study indicates the presence of a strong oxidative stress in children with asthma that increases with the severity of the disease. In this population, val/val genotype at GSTP1 ile105val locus may be an important factor in determining the degree of oxidant injury.

Clinical implications

Children with asthma with val/val genotype at GSTP1 ile105val locus may be good candidates for supplemental antioxidant therapy.

Section snippets

Patients with asthma

The patients in the asthma group have been detailed previously.36, 37 Each child with asthma was then classified according to the severity of asthma precisely as detailed in Global Initiative for Asthma guidelines38 and as detailed previously.36, 37

From this cohort of white children with asthma, samples of 200 children with mild asthma age 6 to 16 years who were not receiving any controller medication and who had not had any symptoms of lower or upper respiratory tract infection or asthma

Results

Two hundred children with mild asthma, 118 children with moderate-severe asthma, and 187 healthy controls in control group 1 and 68 children in control group 2 were initially included in the study. The study population consisted of 196 children with mild asthma, 116 children with moderate-severe asthma (107 moderate and 9 severe), and all healthy controls who could be successfully genotyped in at least 1 locus. Characteristics of the study population are summarized in Table I. There was a

Discussion

Our study indicates that asthma is associated with a strong systemic oxidative stress that increases in parallel with the severity of the disease. The sharp increase in the oxidant stress is clearly evident from the fact that there is only very little overlap in the malondialdehyde and reduced glutathione levels between the population with asthma and healthy controls. The increased oxidative burden is a result both of increased oxidative stress as evidenced by increased malondialdehyde and of

References (54)

  • F.D. Gilliland et al.

    Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study

    Lancet

    (2004)
  • J. Sandstrom et al.

    10-fold increase in human plasma extracellular superoxide dismutase content caused by a mutation in heparin-binding domain

    J Biol Chem

    (1994)
  • Y. Saraclar et al.

    Prevalence of asthmatic phenotypes and bronchial hyperresponsiveness in Turkish schoolchildren: an International Study of Asthma and Allergies in Childhood (ISAAC) phase 2 study

    Ann Allergy Asthma Immunol

    (2003)
  • M.A. Baker et al.

    Microtiter plate assay for the measurement of glutathione and glutathione disulfide in large numbers of biological samples

    Anal Biochem

    (1990)
  • S. Campo et al.

    Extracellular superoxide dismutase (EC-SOD) gene mutations screening in a sample of Mediterranean population

    Mutat Res

    (2005)
  • M. Saadat et al.

    Combination of CC16, GSTM1, and GSTT1 genetic polymorphisms is associated with asthma

    J Allergy Clin Immunol

    (2004)
  • X. Hu et al.

    Activity of four allelic forms of glutathione S-transferase hGSTP1-1 for diol epoxides of polycyclic aromatic hydrocarbons

    Biochem Biophys Res Commun

    (1997)
  • A.M. Vignola et al.

    Airway inflammation in mild intermittent and in persistent asthma

    Am J Respir Crit Care Med

    (1998)
  • A.A. Andreadis et al.

    Oxidative and nitrosative events in asthma

    Free Radic Biol Med

    (2003)
  • S. Owen et al.

    Evidence of free-radical activity in asthma

    N Engl J Med

    (1991)
  • M.A. Spiteri et al.

    Polymorphisms at the glutathione S-transferase, GSTP1 locus: a novel mechanism for susceptibility and development of atopic airway inflammation

    Allergy

    (2000)
  • M. Ichinose et al.

    Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways

    Am J Respir Crit Care Med

    (2000)
  • W.J. Calhoun et al.

    Enhanced superoxide production by alveolar macrophages and air-space cells, airway inflammation, and alveolar macrophage density changes after segmental antigen bronchoprovocation in allergic subjects

    Am Rev Respir Dis

    (1992)
  • S.P. Sanders et al.

    Spontaneous oxygen radical production at sites of antigen challenge in allergic subjects

    Am J Respir Crit Care Med

    (1995)
  • P. Demoly et al.

    IFN-gamma activates superoxide anion production in blood monocytes from allergic asthmatic patients

    Ann Allergy Asthma Immunol

    (1995)
  • D.J. Evans et al.

    Priming of circulating human eosinophils following late response to allergen challenge

    Eur Respir J

    (1996)
  • X.Y. Li et al.

    An investigation of the role of glutathione in increased epithelial permeability induced by cigarette smoke in vivo and in vitro

    Am J Respir Crit Care Med

    (1994)

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    Supported by Hacettepe University grant #02 02 101 020.

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

    ∗

    These authors contributed equally to this article.

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    Copyright © 2006 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved.