Asthma and Oxidative Stress

Advances in Autism Research
compiled by Teresa Binstock for ARI
April 2008

1. Oxidative stress and genetic and epidemiologic determinants of oxidant injury in childhood asthma

Ercan H et al.
J Allergy Clin Immunol. 2006 Nov;118(5):1097-104.

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.
PMID: 17088135

2. Oxidative stress in the pathogenesis of asthma

Bowler RP.
Curr Allergy Asthma Rep. 2004 Mar;4(2):116-22.

Asthma affects 5% to 10% of the population of the United States. In asthmatics, oxidative stress occurs not only as a result of inflammation but also from environmental exposure to air pollution. The specific localization of antioxidants in the lung and the adaptive changes during asthma underscore the importance of oxidative stress, and therapeutic interventions that decrease exposure to environmental reactive oxygen species or augment endogenous antioxidant defenses might be beneficial as adjunctive therapies in asthmatic patients.
PMID: 14769260

3. Sleep disturbances and correlates of children with autism spectrum disorders

Liu X, Hubbard JA, Fabes RA, Adam JB.
Child Psychiatry Hum Dev. 2006 Winter;37(2):179-91.

This study examined sleep patterns, sleep problems, and their correlates in children with autism spectrum disorders (ASD). Subjects consisted of 167 ASD children, including 108 with autistic disorder, 27 with Asperger's syndrome, and 32 with other diagnoses of ASD. Mean age was 8.8 years (SD = 4.2), 86% were boys. Parents completed a self-administered child sleep questionnaire. Results showed that average night sleep duration was 8.9 h (SD = 1.8), 16% of children shared a bed with parent. About 86% of children had at least one sleep problem almost every day, including 54% with bedtime resistance, 56% with insomnia, 53% with parasomnias, 25% with sleep disordered breathing, 45% with morning rise problems, and 31% with daytime sleepiness. Multivariate logistic regression analyses indicated that younger age, hypersensitivity, co-sleeping, epilepsy, attention-deficit/hyperactivity disorder (ADHD), asthma, bedtime ritual, medication use, and family history of sleep problems were related to sleep problems. Comorbid epilepsy, insomnia, and parasomnias were associated with increased risk for daytime sleepiness. Results suggest that both dyssomnias and parasomnias are very prevalent in children with ASD. Although multiple child and family factors are associated with sleep problems, other comorbid disorders of autism may play a major role.
PMID: 17001527

4. Importance of oxidative stress in the pathogenesis and treatment of asthma

Riedl MA, Nel AE.
Curr Opin Allergy Clin Immunol. 2008 Feb;8(1):49-56.

PURPOSE OF REVIEW: The purpose of the current review is to summarize recent evidence demonstrating the important role of oxidative stress in asthma pathogenesis. The therapeutic implications of these findings will be presented. RECENT FINDINGS: Mechanistically, the effect of oxidative stress on dendritic cells has been demonstrated to have a potent effect on Th1/Th2 skewing of the immune response. Investigations of gene-environment interactions have identified genetic polymorphisms associated with individual susceptibility to pollutant-induced respiratory oxidative stress. The effects of current asthma therapy on oxidative stress are currently unclear, but previous trials using conventional antioxidant therapy in asthma have been largely ineffective. Recent investigations have identified two promising broad-based therapeutic approaches: Nrf2 pathway activation and the use of thiol precursors. Preliminary data suggest that fullerene nanomaterials and dietary interventions may also have potential benefits in asthma. SUMMARY: Our current understanding of the role of oxidative stress in asthma suggests that antioxidant therapy may be important in optimizing asthma treatment and prevention. The future success of antioxidant asthma therapy will require strategies with broad effects on airway redox equilibrium and the selection of appropriate target populations.
PMID: 18188018

5. Oxidative and nitrative stress in bronchial asthma

Sugiura H, Ichinose M.
Antioxid Redox Signal. 2008 Apr;10(4):785-97.

There has been a marked increase in the global prevalence, morbidity, and mortality of asthma, and its associated economic burden has also grown over the last 40 years. Approximately 300 million people worldwide currently have asthma, and its prevalence increases by 50% every decade. Airway inflammation is the most proximate cause of the recurrent episodes of airflow limitation in asthma. Recent research has revealed that numerous biologically active proinflammatory mediators are responsible for the pathogenesis of asthma. Among these mediators, there is increasing evidence that endogenous or exogenous reactive oxygen species (ROS) and reactive nitrogen species (RNS) are responsible for the airway inflammation of asthma. Many reports have shown that there is an excessive production of ROS and RNS in the airways of asthmatic individuals compared with healthy subjects. Excessively produced ROS and RNS have been reported to lead to airway inflammation, airway hyper-responsiveness, airway microvascular hyperpermeability, tissue injury, and remodeling in animal models and human studies. Although human lungs have a potent antioxidant system, excessive oxidative and nitrative stress leads to an imbalance of oxidants/antioxidants. This review describes the rapidly accruing data linking oxidative and nitrative events to the pathogenesis of bronchial asthma.
PMID: 18177234

6. Antioxidants, oxidative stress, and pulmonary function in individuals diagnosed with asthma or COPD

Ochs-Balcom HM et al.
Eur J Clin Nutr. 2006 Aug;60(8):991-9. Epub 2006 Feb 15.

OBJECTIVE: The objective of this study was to investigate the association between antioxidant nutrients and markers of oxidative stress with pulmonary function in persons with chronic airflow limitation. DESIGN: Cross-sectional study exploring the association of antioxidant nutrients and markers of oxidative stress with forced expiratory volume in the first second (FEV1%) and forced vital capacity (FVC%). SETTING/SUBJECTS: The study data included 218 persons with chronic airflow limitation recruited randomly from the general population of Erie and Niagara counties, New York State, USA. RESULTS: After adjustment for covariates, multiple linear regression analysis showed that serum beta-cryptoxanthin, lutein/zeaxanthin, and retinol, and dietary beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, vitamin C, and lycopene were positively associated with FEV1% (P < 0.05, all associations). Serum vitamins beta-cryptoxanthin, lutein/zeaxanthin, and lycopene, and dietary beta-cryptoxanthin, beta-carotene, vitamin C, and lutein/zeaxanthin were positively associated with FVC% (P < 0.05, all associations). Erythrocytic glutathione was negatively associated with FEV1%, while plasma thiobarbituric acid-reactive substances (TBARS) were negatively associated with FVC% (P < 0.05). CONCLUSION: These results support the hypothesis that an imbalance in antioxidant/oxidant status is associated with chronic airflow limitation, and that dietary habits and/or oxidative stress play contributing roles.
PMID: 16482071

7. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy

Kirkham P, Rahman I.
Pharmacol Ther. 2006 Aug;111(2):476-94. Epub 2006 Feb 3.

Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory lung diseases that are characterized by systemic and chronic localized inflammation and oxidative stress. Sources of oxidative stress arise from the increased burden of inhaled oxidants, as well as elevated amounts of reactive oxygen species (ROS) released from inflammatory cells. Increased levels of ROS, either directly or via the formation of lipid peroxidation products, may play a role in enhancing the inflammatory response in both asthma and COPD. Moreover, in COPD it is now recognized as the main pathogenic factor for driving disease progression and increasing severity. ROS and lipid peroxidation products can influence the inflammatory response at many levels through its impact on signal transduction mechanisms, activation of redox-sensitive transcriptions factors, and chromatin regulation resulting in pro-inflammatory gene expression. It is this impact of ROS on chromatin regulation by reducing the activity of the transcriptional co-repressor, histone deacetylase-2 (HDAC-2), that leads to the poor efficacy of corticosteroids in COPD, severe asthma, and smoking asthmatics. Thus, the presence of oxidative stress has important consequences for the pathogenesis, severity, and treatment of asthma and COPD. However, for ROS to have such an impact, it must first overcome a variety of antioxidant defenses. It is likely, therefore, that a combination of antioxidants may be effective in the treatment of asthma and COPD. Various approaches to enhance the lung antioxidant screen and clinical trials of antioxidant compounds are discussed.
PMID: 16458359

8. Oxidative stress and antioxidant deficiencies in asthma: potential modification by diet

Misso NL, Thompson PJ.
Redox Rep. 2005;10(5):247-55.

The lungs of asthmatic patients are exposed to oxidative stress due to the generation of reactive oxygen and nitrogen species as a consequence of chronic airway inflammation. Increased concentrations of NO*, H2O2 and 8-isoprostane have been measured in exhaled breath and induced sputum of asthmatic patients. O2*-, NO*, and halides interact to form highly reactive species such as peroxynitrite and HOBr, which in turn cause nitration and bromination of protein tyrosine residues. Oxidative stress may also reduce glutathione levels and cause inactivation of antioxidant enzymes such as superoxide dismutase, with a consequent increase in apoptosis, shedding of airway epithelial cells and airway remodelling. The oxidant/antioxidant equilibrium in asthmatic patients may be further perturbed by low dietary intakes of the antioxidant vitamins C and E, selenium and flavonoids, with a consequent lowering of the concentrations of these and other non-dietary antioxidants such as bilirubin and albumin in plasma and airway epithelial lining fluid. Although supplementation with vitamins C and E appears to offer protection against the adverse effects of ozone, recent randomised, placebo-controlled trials of vitamin C or E supplements for patients with mild asthma have not shown significant benefits over standard therapy. However, genetic variation in glutathione S-transferase may influence the susceptibility of asthmatic individuals to oxidative stress and the extent to which they are likely to benefit from antioxidant supplementation. Long-term prospective trials are required to determine whether modification of dietary intake will benefit asthma patients and reduce the socio-economic burden of asthma in the community.
PMID: 16354413

9. Glutathione S-transferase P1, maternal smoking, and asthma in children: a haplotype-based analysis

Li YF et al.
Environ Health Perspect. 2008 Mar;116(3):409-15.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2265034&blobtype=pdf

BACKGROUND: Glutathione S-transferase P1 (GSTP1) plays a role in a spectrum of respiratory diseases; however, the effects of sequence variation across the entire locus in asthma pathogenesis have yet to be determined. OBJECTIVES: This study was designed to investigate whether sequence variations in the GSTP1 coding and promoter regions are associated with asthma and wheezing outcomes and to determine whether variants affect susceptibility to maternal smoking. METHODS: Four haplotype tagging SNPs were selected that accounted for 83% of the common haplotypic variation in GSTP1. The associations of GSTP1 variants with asthma and wheezing were assessed among white children in the Children's Health Study (CHS). RESULTS: The Ile105Val allele and a SNP in the upstream promoter region (SNP1: rs6591255, putative transcription factor 1 binding site) were associated with asthma and wheezing outcomes, an association observed in two cohorts of the CHS recruited in different years. Haplotypes that included both the promoter SNP (i.e., rs6591255) and the 105 Val variant were associated with an increased risk for asthma in non-Hispanic whites. Using SNP- and haplotype-based approaches, the effect of maternal smoking on wheezing was largest in children with the Ile105Val allele. CONCLUSIONS: Variants in both the promoter and coding regions of the GSTP1 locus may contribute to the occurrence of childhood asthma and wheezing and may increase susceptibility to adverse effects of tobacco-smoke exposure.
PMID: 18335111

10. Oxidized vitamin E and glutathione as markers of clinical status in asthma

Wood LG et al.
Clin Nutr. 2008 Jan 28 [Epub ahead of print]

BACKGROUND & AIMS: Antioxidant status is disturbed in asthma. Measurement of both oxidized and reduced forms of antioxidants provides important information regarding the oxidant/antioxidant balance. The aim of this study was to investigate the clinical relevance of key antioxidants (alpha-tocopherol and glutathione) in asthma, by measuring the oxidized and reduced forms, in the airways (induced sputum) and systemically (peripheral blood). METHODS: This cross-sectional study examines stable asthmatics (n=44) and healthy controls (n=31) recruited through John Hunter Hospital, NSW, Australia. We collected peripheral blood and induced sputum during hypertonic saline challenge. alpha-tocopherol and alpha-tocopherol quinone were measured by HPLC. Total glutathione and glutathione disulfide were determined by a colorimetric assay. RESULTS: Plasma alpha-tocopherol was low in asthma versus controls. Subjects with asthma had higher levels of whole blood alpha-tocopherol quinone and %alpha-tocopherol quinone than controls and %alpha-tocopherol quinone correlated with asthma control (p=0.009). Sputum supernatant levels of total, reduced and oxidized glutathione were elevated in asthma versus controls. Oxidized glutathione in sputum supernatant negatively correlated with FEV(1)/FVC% (p=0.029). CONCLUSIONS: In asthma, both systemic and airway antioxidant defences are disturbed. Oxidized forms of alpha-tocopherol and glutathione are associated with clinical asthma outcomes, and should be further investigated as a tool for monitoring asthma.
PMID: 18234400

11. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma

Johnson JB et al.
Free Radic Biol Med. 2007 Mar 1;42(5):665-74. Epub 2006 Dec 14.

Asthma is an increasingly common disorder responsible for considerable morbidity and mortality. Although obesity is a risk factor for asthma and weight loss can improve symptoms, many patients do not adhere to low calorie diets and the impact of dietary restriction on the disease process is unknown. A study was designed to determine if overweight asthma patients would adhere to an alternate day calorie restriction (ADCR) dietary regimen, and to establish the effects of the diet on their symptoms, pulmonary function and markers of oxidative stress, and inflammation. Ten subjects with BMI>30 were maintained for 8 weeks on a dietary regimen in which they ate ad libitum every other day, while consuming less than 20% of their normal calorie intake on the intervening days. At baseline, and at designated time points during the 8-week study, asthma control, symptoms, and Quality of Life questionnaires (ACQ, ASUI, mini-AQLQ) were assessed and blood was collected for analyses of markers of general health, oxidative stress, and inflammation. Peak expiratory flow (PEF) was measured daily on awakening. Pre- and postbronchodilator spirometry was obtained at baseline and 8 weeks. Nine of the subjects adhered to the diet and lost an average of 8% of their initial weight during the study. Their asthma-related symptoms, control, and QOL improved significantly, and PEF increased significantly, within 2 weeks of diet initiation; these changes persisted for the duration of the study. Spirometry was unaffected by ADCR. Levels of serum beta-hydroxybutyrate were increased and levels of leptin were decreased on CR days, indicating a shift in energy metabolism toward utilization of fatty acids and confirming compliance with the diet. The improved clinical findings were associated with decreased levels of serum cholesterol and triglycerides, striking reductions in markers of oxidative stress (8-isoprostane, nitrotyrosine, protein carbonyls, and 4-hydroxynonenal adducts), and increased levels of the antioxidant uric acid. Indicators of inflammation, including serum tumor necrosis factor-alpha and brain-derived neurotrophic factor, were also significantly decreased by ADCR. Compliance with the ADCR diet was high, symptoms and pulmonary function improved, and oxidative stress and inflammation declined in response to the dietary intervention. These findings demonstrate rapid and sustained beneficial effects of ADCR on the underlying disease process in subjects with asthma, suggesting a novel approach for therapeutic intervention in this disorder.
PMID: 17291990