Advances in Autism Research
compiled by Teresa Binstock for
Autism Research Institute
April 2008
Asthma and Oxidative Stress
see also
Oxidative stress and autism
Pollutants and oxidative stress
Pollutants and autism
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
see also