Oxidative stress and its determinants in the airways of children with asthma

Background: There is ample evidence for the existence of a systemic oxidative stress in childhood asthma but relatively little information on the oxidant stress in the airways. Objective: To determine the extent of oxidant/antioxidant imbalance and describe its determinants in the airways of asthmatic children including asthma severity and the genotype of the antioxidant enzymes. Methods: One hundred and ten children with mild asthma, 30 children with moderate asthma and 191 healthy controls were included in the study. Exhaled breath condensate (EBC) was collected from all children with EcoScreen^®. Levels of malondialdehyde were measured as the indicator of oxidative stress, and of reduced glutathione as the indicator of antioxidant defense. Children were genotyped for the presence of null variants of glutathione S transferase (GST) T1 and GSTM1, and ile105val variant of GSTP1. Risk factors were analyzed with multivariate logistic regression. Results: EBC contained significantly higher levels of malondialdehyde and lower levels of reduced glutathione in asthmatic children compared with healthy controls (P < 0.001 for each), whereas there was no difference between mild and moderate asthmatics. Multivariate logistic regression identified asthma as the only independent factor contributing to oxidative stress. Genotypes of the antioxidant enzymes had no effect on the oxidative burden. Conclusions: Asthma is associated with an extremely powerful oxidative stress not only in the systemic circulation but also in the airways.     

Oxidative stress is associated with atopic indices in relation to childhood rhinitis and asthma

BackgroundThe association between oxidative stress and atopic diseases is uncertain. Several risk factors for atopic diseases have been identified, however, a comprehensive investigation of the relationship between oxidative stress markers and atopic indices related to atopic diseases is currently lacking.MethodsWe investigated 132 children who completed a 7-years follow-up in a birth cohort. Oxidative stress markers including plasma glutathione peroxidase (GPx), myeloperoxidase (MPO), total anti-oxidant capacity (TAC), and urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels were measured. Allergen-specific IgE levels, FeNO levels, and pulmonary function tests were also obtained.ResultsThe activity of GPx and levels of MPO were inversely correlated to food (shrimp and crab) and house dust mite sensitization respectively. The 8-OHdG levels were strongly negatively correlated with FeNO levels (p < 0.01). A significant positive correlation was found between TAC levels and pre-and post-bronchodilator FVC % and FEV1% predicted (p < 0.05). All oxidative stress markers were not associated with the risk of atopic diseases. However, GPx-related crab sensitization and 8-OHdG related FeNO levels were significantly associated with increased risk of allergic rhinitis, while MPO-related mite sensitization and TAC-related pulmonary function parameters were strongly associated with risk of asthma (p < 0.01).ConclusionOxidative stress is strongly correlated with allergic indices, potentially playing a role in the modulation of allergic responses contributing to atopic diseases.     

Oxidative and nitrative stress in bronchial asthma

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.     

氧化应激与脑缺血-再灌注损伤

脑缺血-再灌注损伤是一个复杂的级联反应过程,涉及多种机制,其中氧化应激起到关键作用。目前的研究表明,氧化应激可以通过脂质过氧化、蛋白质变性和/或DNA修饰等途径促使神经细胞坏死,也可以通过线粒体、内质网或死亡受体等途径启动神经细胞凋亡。本文就氧化应激在脑缺血-再灌注损伤中的作用机制及抗氧化治疗的新进展作一综述。     

The relationship of psychologic stress with childhood asthma

The psychologic influence on childhood asthma has long been a subject of investigation and controversy. This article illustrates the evidence that psychologic stress is related to children with asthma. Individual experience, the impact of family and neighborhood, the effect of caregiver mental status, and the presence of negative psychologic events affect symptoms and management. The pathways through which these factors influence asthma are mediated through cognitive and biologic mechanisms, with evidence indicating changes in behavior and alteration in immune response as underlying mechanisms. Psychologic issues are important in the patient with severe asthma. The mind-body paradigm that links psychologic stress to disease is necessary when considering the global evaluation of childhood asthma.     

Cross-talk between pulmonary injury, oxidant stress, and gap junctional communication

Gap junction channels interconnect several different types of cells in the lung, ranging from the alveolar epithelium to the pulmonary vasculature, each of which expresses a unique subset of gap junction proteins (connexins). Major lung functions regulated by gap junctional communication include coordination of ciliary beat frequency and inflammation. Gap junctions help enable the alveolus to regulate surfactant secretion as an integrated system, in which type I cells act as mechanical sensors that transmit calcium transients to type II cells. Thus, disruption of epithelial gap junctional communication, particularly during acute lung injury, can interfere with these processes and increase the severity of injury. Consistent with this, connexin expression is altered during lung injury, and connexin-deficiency has a negative impact on the injury response and lung-growth control. It has recently been shown that alcohol abuse is a significant risk factor associated with acute respiratory distress syndrome. Oxidant stress and hormone-signaling cascades in the lung induced by prolonged alcohol ingestion are discussed, as well as the effects of these pathways on connexin expression and function.     

Lack of association between genetic variation in G-protein-coupled receptor for asthma susceptibility and childhood asthma and atopy

G-protein-coupled receptor for asthma susceptibility (GPRA or GPR154) was identified as an asthma and atopy candidate gene by positional cloning. Some subsequent studies suggest associations of GPRA single nucleotide polymorphisms (SNPs) and haplotypes with asthma or atopy susceptibility. However, the associated SNPs or haplotypes vary among studies. The role of GPRA genetic variation in asthma and atopy remains unsolved. Published data on GRPA variants and asthma come exclusively from Caucasian and Asian populations. We examined whether GPRA SNPs and haplotypes are associated with asthma and atopy in a Mexican population. We genotyped and analyzed 27 GPRA SNPs in 589 nuclear families consisting of asthmatic children aged 4-17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests to 25 aeroallergens. The 27 SNPs examined provided excellent coverage of the GPRA gene. GPRA SNPs and haplotypes were not associated with childhood asthma and the degree of atopy to aeroallergens in a Mexican population. Our review of studies of GPRA variants in relation to asthma phenotypes shows considerable heterogeneity. Accordingly, our results suggest that GPRA variants are not an important contributor to childhood asthma and atopy susceptibility in a Mexican population.     

Vascular oxidant stress and inflammation in hyperhomocysteinemia

Elevated plasma levels of homocysteine are a metabolic risk factor for atherosclerotic vascular disease, as shown in numerous clinical studies that linked elevated homocysteine levels to de novo and recurrent cardiovascular events. High levels of homocysteine promote oxidant stress in vascular cells and tissue because of the formation of reactive oxygen species (ROS), which have been strongly implicated in the development of atherosclerosis. In particular, ROS have been shown to cause endothelial injury, dysfunction, and activation. Elevated homocysteine stimulates proinflammatory pathways in vascular cells, resulting in leukocyte recruitment to the vessel wall, mediated by the expression of adhesion molecules on endothelial cells and circulating monocytes and neutrophils, in the infiltration of leukocytes into the arterial wall mediated by increased secretion of chemokines, and in the differentiation of monocytes into cholesterol-scavenging macrophages. Furthermore, it stimulates the proliferation of vascular smooth muscle cells followed by the production of extracellular matrix. Many of these events involve redox-sensitive signaling events, which are promoted by elevated homocysteine, and result in the formation of atherosclerotic lesions. In this article, we review current knowledge about the role of homocysteine on oxidant stress-mediated vascular inflammation during the development of atherosclerosis.     

Socioeconomic status and inflammatory processes in childhood asthma: the role of psychological stress

BACKGROUND: Although social environment variables such as socioeconomic status (SES) have been linked to childhood asthma, little is known about the psychobiological mechanisms underlying this relationship. OBJECTIVES: The goal of this study was to investigate relationships among SES, psychological stress, and immune processes implicated in asthma. METHODS: Thirty-seven children ages 9 to 18 years, physician-diagnosed with asthma, and 39 healthy children participated. Families were interviewed about chronic life stress, perceptions of threat, and SES. Blood samples were drawn from children to assess stimulated production of cytokines implicated in asthma (IL-4, IL-5, IL-13) and eosinophil counts. RESULTS: In children with asthma, lower SES was associated with heightened production of IL-5 and IL-13 and higher eosinophil counts (P values < .05). Lower SES also was associated with higher chronic stress and perceived threat (both groups: P values < .05). Higher levels of stress and threat perception were associated with heightened production of IL-5 and IL-13, and higher eosinophil counts in children with asthma (P values < .05). Statistical mediation tests revealed that chronic stress and threat perception represented statistically significant pathways between SES and immune processes in children with asthma (P values < .05). In healthy children, associations were in the opposite direction from the asthma group, though generally not significant. CONCLUSION: This is one of the first studies to document empirically a psychobiological explanation for the epidemiologic relationship between low SES and poor asthma outcomes. CLINICAL IMPLICATIONS: Associations among SES, psychological stress, and immune pathways suggest that the experience of stress, particularly among lower SES children, has implications for childhood asthma morbidity.     

Multimodal patient education program with stress management for childhood and adolescent asthma

The present study aimed to evaluate a multimodal patient education program carried out during inpatient rehabilitation. The program included cognitive-behavioral stress management training as a main component. The efficacy was examined in comparison to an education program without stress management. In total N=68 patients aged between 8 and 16 years were included in the post-treatment and N=46 patients in the 6 months follow-up assessment. Short- and long-term intervention effects of the multimodal education program were observed in relation to patients' age. The experimental treatment elicited significant improvements in adaptive coping in adolescents aged from 14 to 16 years. In contrast, substantial effects were not yielded for the control treatment. The results suggest that the multimodal patient education training has beneficial effects on stress management in adolescents with asthma. Results are discussed with regard to predictive factors for rehabilitation outcome.     

ATP and microfilaments in cellular oxidant injury.

Oxidant injury produces dramatic changes in cytoskeletal organization and cell shape. ATP synthetic pathways are major targets of oxidant injury resulting in rapid depletion of cellular ATP following oxidant exposure. The relation of ATP depletion to the changes in microfilament organization seen following H2O2 exposure were examined in the P388D1 cell line. Three hours of glucose depletion alone resulted in a decline in cellular ATP levels to less than 10% of controls, which was comparable to ATP levels in cells 30 to 60 minutes after exposure to 5 mM H2O2 in the presence of glucose. Adherent cells stained with rhodamine phalloidin, a probe specific for polymerized (F) actin, revealed a progressive shortening of microfilaments into globular aggregates within cells depleted of glucose over 3 hours, a pattern similar to earlier observations of H2O2-injured cells after 1 hour. The changes in cellular ATP associated with glucose depletion or H2O2 exposure were then correlated with G actin content measured by the DNAse 1 inhibition assay. No real differences in G actin content as a percentage of total actin were seen in P388D1 cells following 3 hours of glucose depletion or 30 to 60 minutes after exposure to 5 mM H2O2. But 2 to 3 hours after exposure to H2O2 there was a progressive decrease in G actin as a percentage of total actin within the cells. Transmission electron microscopy of cells depleted of glucose for 3 h or 1 hour after exposure to H2O2 revealed the presence of side-to-side aggregates or bundles of microfilaments within the cells. These observations suggest that declining levels of ATP either from metabolic inhibition or H2O2 injury are correlated with the fragmentation and shortening of microfilaments into aggregates. No net change in monomeric or polymeric actin was necessary for this to occur. However, at later time points after H2O2 exposure some actin assembly did occur.     

Prevention of asthma in childhood

PURPOSE OF REVIEW: The prevalence of asthma is increasing in many parts of the world, particularly in developed countries. The present review focuses on recent literature regarding asthma prevention in childhood. RECENT FINDINGS: Several environmental exposures in infancy or early childhood are associated with reduced prevalence of asthma, but the mechanisms leading to these associations remain unknown. Recent studies have demonstrated limited success in the prevention of asthma or asthma symptoms with the use of asthma medications, once the therapy is discontinued. Immunotherapy offers another strategy for asthma prevention, and groups treated with this intervention have demonstrated reduced atopy and asthma. Several multi-interventional trials have demonstrated a reduced asthma symptom burden but have not demonstrated significant differences in objective measures such as lung function or bronchial hyper-responsiveness between intervention groups. SUMMARY: The most promising asthma prevention strategies to date have been those that use a multi-interventional approach employing both dietary and environmental manipulations. More research is needed to assess the long-term follow-up of multi-interventional trials and to evaluate novel intervention strategies in the primary or secondary prevention of asthma in childhood.     

Progression of asthma in childhood

In general, asthma runs a variable course. However, there are children with asthma who are at risk for progressive disease that can lead to failure to attain peak lung growth and eventually can result in clinical and functional impairment. We present a case of a 14-year-old girl who has demonstrated a deterioration in lung function at least in the past 6 years. This has been associated with increasing medication requirements, including chronic oral corticosteroid and a steroid-sparing medication, the presence of comorbidities, and the occurrence of frequent exacerbations. The patient has evidence of airway inflammation and remodeling based on biomarkers and biopsy findings. It remains a challenge to determine patients at risk for irreversible airflow obstruction, presumably a result of airway remodeling. Histopathologic studies from biopsy samples provide the best evidence for this. However, bronchoscopy and biopsy require technical expertise and cannot be routinely used. Clinically, once a patient increases medication requirements, this should serve as a marker of disease progression. Biomarkers of airway inflammation such as exhaled nitric oxide, exhaled breath condensates, and induced sputum analysis may have the potential to monitor disease progression. Additional efforts are necessary to understand the mechanisms involved in this phenomenon and to discover specific modalities of treatment to target the structural changes of airway remodeling.