Stress In Asthma Research Articles

IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma.

Quantification of type 2 inflammation provided a molecular basis for heterogeneity in asthma. Non-type 2 pathways that contribute to asthma pathogenesis are not well understood. To identify dysregulated pathways beyond type 2 inflammation. We applied RNA sequencing to airway epithelial brushings obtained from subjects with stable mild asthma not on corticosteroids (n = 19) and healthy control subjects (n = 16). Sequencing reads were mapped to human and viral genomes. In the same cohort, and in a separate group with severe asthma (n = 301), we profiled blood gene expression with microarrays. In airway brushings from mild asthma on inhaled corticosteroids, RNA sequencing yielded 1,379 differentially expressed genes (false discovery rate < 0.01). Pathway analysis revealed increased expression of type 2 markers, IFN-stimulated genes (ISGs), and endoplasmic reticulum (ER) stress-related genes. Airway epithelial ISG expression was not associated with type 2 inflammation in asthma or with viral transcripts but was associated with reduced lung function by FEV1 (ρ = -0.72; P = 0.0004). ER stress was confirmed by an increase in XBP1 (X-box binding protein 1) splicing in mild asthma and was associated with both type 2 inflammation and ISG expression. ISGs were also the most activated genes in blood cells in asthma and were correlated with airway ISG expression (ρ = 0.55; P = 0.030). High blood ISG expression in severe asthma was similarly unrelated to type 2 inflammation. ISG activation is prominent in asthma, independent of viral transcripts, orthogonal to type 2 inflammation, and associated with distinct clinical features. ER stress is associated with both type 2 inflammation and ISG expression.

Biomarkers in adult asthma: a systematic review of 8-isoprostane in exhaled breath condensate

Objectives. We aimed to assess the evidence for the use of 8-isoprostane in exhaled breath condensate (EBC) as a biomarker in adult asthma. Design. A systematic review and meta-analysis of EBC 8-isoprostane. Methods. We searched a number of online databases (including PubMed, Embase and Scopus) in January 2016. We included studies of adult non-smokers with EBC collection and asthma diagnosis conducted according to recognised guidelines. We aimed to pool data using random effects meta-analysis and assess heterogeneity using I2. Results. We included twenty studies, the findings from which were inconsistent. Seven studies (n = 329) reported 8-isoprostane levels in asthma to be significantly higher than that of control groups, whilst six studies (n = 403) did not. Only four studies were appropriate for inclusion in a random effects meta-analysis of mean difference. This found a statistically significant between-groups difference of 22 pg ml−1. Confidence in the result is limited by the small number of studies and by substantial statistical heterogeneity (I2 = 94). Conclusion. The clinical value of EBC 8-isoprostane as a quantitative assessment of oxidative stress in asthma remains unclear due to variability in results and methodological heterogeneity. It is essential to develop a robust and standardised methodology if the use of EBC 8-isoprostane in asthma is to be properly evaluated.

Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma

In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress) and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG) and wild-type (WT) C57BL/6J mice exposed to ovalbumin (OVA), Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13) induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85α/Akt pathway and NFκB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFκB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma.

Study of mitochondrial DNA alteration in the exhaled breath condensate of patients affected by obstructive lung diseases

Mitochondrial DNA (MtDNA) has been studied as an expression of oxidative stress in asthma, COPD, lung cancer and obstructive sleep apnea, but it has been mainly investigated systemically, although the pathogenetic mechanisms begin in the airways and only later progress to systemic circulation. The aim of this study was to investigate the MtDNA alterations in the exhaled breath condensate (EBC) of patients with asthma, COPD and asthma-COPD overlap syndrome (ACOS). In order to analyze better what happens to mitochondria, both locally and systemically, we compared MtDNA/nDNA in blood and EBC of paired patients.Thirteen (13) COPD patients, 14 asthmatics, 23 ACOS (10 according to Spanish guidelines, 13 in line with GINA guidelines) and 12 healthy subjects were enrolled. Patients underwent clinical and functional diagnostic tests as foreseen by the guidelines. They underwent blood and EBC collection. Content of MtDNA and nuclear DNA (nDNA) was measured in the blood cells and EBC of patients by Real Time PCR. The ratio between MtDNA/nDNA was calculated.For the first time we were able to detect MtDNA/nDNA in the EBC. We found higher exhaled MtDNA/nDNA in COPD, asthmatic and ACOS patients respectively compared to healthy subjects (21.9 ± 4.9 versus 6.51 ± 0.21, p < 0.05; 7.9 ± 2.5 versus 6.51 ± 0.21, p = 0.06; 18.3 ± 3.4 versus 6.51 ± 0.21, p < 0.05). The level of exhaled MtDNA/nDNA was positively correlated with the plasmatic one.The levels of MtDNA/nDNA in the EBC, as expression of oxidative stress, are increased in COPD, asthmatic and ACOS patients compared to healthy subjects. These are preliminary results in a small number of well characterized patients that requires confirmation on a larger population. We support new studies directed toward the analysis of exhaled MtDNA/nDNA as a new exhaled non-invasive marker in other inflammatory/oxidative airways diseases.

Cortisol response to acute stress in asthma: Moderation by depressive mood

Both individuals with asthma and depression show signs of a dysregulated hypothalamus-pituitary-adrenal axis. However, little is known about the cortisol response to stress in the context of co-occurring asthma and depressive mood. Thirty-nine individuals with asthma and 41 healthy controls underwent a combined speech and mental arithmetic stressor. During the course of the laboratory session, salivary cortisol was collected 5 times, with 1 sample at 0min before the stressor and 4 samples at 0, 15, 30 and 45min after the stressor. Depressive mood in the past week was assessed with the Hospital Anxiety and Depression Scale at the beginning of the session. Depressive symptoms moderated cortisol response to the acute stressor, but only among asthmatic patients. Higher depressive mood was associated with a significant increase in cortisol, whereas low depressive mood was associated with no cortisol response. In healthy participants, depressive mood had no substantial effect on cortisol response to the stressor. These findings suggest that depressive mood and chronic inflammatory diseases such as asthma can interact to augment cortisol response to stress.

Identification of Relationships Between Interleukin 15 mRNA and Brain-Derived Neurotrophic Factor II mRNA Levels With Formal Components of Temperament in Asthmatic Patients.

Asthma is a chronic inflammatory and heterogeneous disease developing mostly through allergic inflammation, which modifies the expression of various cytokines and neurotrophins. Previous studies suggest the involvement of interleukin (IL)-15 in the regulation of immune response in asthma. Brain-derived neurotrophic factor (BDNF) II plays an important role as a regulator of development and survival of neurons as well as maintenance of their physiological activity. Chronic stress associated with asthma and elevated IL-15 mRNA and BDNFII mRNA levels may affect the mood and a subjective sensation of dyspnoea-inducing anxiety. Psychopathological variables and numerous cytokine/neurotrophin interactions influence the formation of temperament and strategies of coping with stress. The aim of the study was to identify the role of IL-15 mRNA and BDNFII mRNA expressions and their effect on components of temperament and strategies of coping with stress in asthmatics. A total of 352 subjects (176 healthy volunteers and 176 asthmatic patients) participated in the study. The Formal Characteristic of Behaviour-Temperament Inventory (FCB-TI), Coping Inventory for Stressful Situations (CISS), Beck Depression Inventory, State-Trait Anxiety Inventory, and Borg Rating of Perceived Exertion (RPE) Scale were applied in all the subjects. The expression of IL-15 and BDNFII gene was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Different levels of IL-15 and BDNFII expressions between healthy volunteers and patients were revealed in the study. IL-15 enhanced the BDNFII mRNA expression among patients with bronchial asthma. The depression level negatively correlated with the BDNFII mRNA expression. This neurotrophin modified the temperament variable. BDNFII significantly affected (proportional relationship) the level of briskness in asthmatic patients. BDNFII might influence the level and style of coping with stress (emotion-oriented style). This hypothesis requires further studies on protein functional models. The obtained data confirms the role of IL-15 and BDNFII in the pathomechanisms of depression and formation of selected traits defining the temperament in asthmatics.

Plasma protein thiols: an early marker of oxidative stress in asthma and chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) and asthma are both characterized by heterogeneous chronic airway inflammation and obstruction as well as oxidative stress (OS). However, it is unknown whether OS occurs in early disease and how to best assess its presence. Plasma OS markers (TBARS, PSH, taurine, GSH, ergothioneine and paraoxonase 1 activity) and lung function tests were measured in patients with mild stable asthma (n = 24) and mild stable COPD (n = 29) and in age- and sex-matched controls. Forced expiratory volume in 1 s (FEV1 ) was associated with age both in patients and control groups. By contrast, FEV1 was positively correlated with PSH only in COPD (ρ = 0·49, P = 0·007). In multiple logistic regression analysis, lower PSH was the only OS marker independently associated with increased odds of both asthma (OR = 0·32, 95% CI 0·13-0·78, P = 0·01) and COPD (OR = 0·50, 95% CI 0·26-0·95, P = 0·03). These findings suggest that proteins -SH are a sensitive OS marker in early COPD and asthma.

Exhaled Nitric Oxide Decreases during Academic Examination Stress in Asthma.

Fractional exhaled nitric oxide (FeNO) is known to vary with multiple endogenous and exogenous factors. Laboratory stress and depressive mood have been associated with altered FeNO levels, but little is known about the susceptibility of FeNO to longer-lasting states of psychological stress in asthma. We sought to study changes in FeNO, lung function, and endogenous cortisol levels in students in a low-stress period during the academic term and in high-stress periods of up to 5 days during final exams. One hundred nine participants (35 with asthma) enrolled in a final examination stress study were assessed during the academic term (low stress) and during final exams (high stress). FeNO, spirometric lung function (FEV1, peak flow), salivary cortisol, and negative affect were measured at three time points. Control variables were medication use, cold symptoms, sex, and age. FeNO decreased substantially from low-stress baseline to the high-stress examination periods, with more pronounced decreases occurring in subjects with asthma (-11.5 ppb) than control subjects (-1.2 ppb). FEV1 decreased in both groups. Negative affect and cortisol increased during final exams, but these increases were smaller in asthma. Greater initial depression and greater cortisol increases were related to larger FeNO decreases during the final exam period, the latter only in asthma. Inhaled corticosteroid use did not affect these changes. Psychological stress and depressive mood are accompanied by decreases in both FeNO and lung function in asthma. Fluctuations related to life stress and mood levels should be considered in FeNO monitoring for asthma.

5-Aminosalicylic Acid attenuates allergen-induced airway inflammation and oxidative stress in asthma

Pro-inflammatory cytokines regulate the magnitude of allergic reactions during asthma. Tumor necrosis factor – alpha (TNF-α), interleukin-6 (IL-6) and interleukin-13 (IL-13) play a crucial role in aggravating the inflammatory conditions during allergic asthma. In addition, oxidative stress contributes to the pathogenesis of asthma by altering the physiological condition resulting in the development of status asthmaticus. Anti-inflammatory corticosteroids are being widely used for treating allergic asthma. In the present study 5-aminosalicylic acid (5-ASA), a salicylic acid derivative, was evaluated, in vivo for its potential to suppress TNF-α, IL-6 and IL-13 using ovalbumin (OVA) induced allergic asthma in Balb/C mice. Oral administration of 65, 130 and 195 mg/kg 5-ASA significantly reduced the OVA induced total and differential leucocyte count, TNF-α, IL-6, IL-13, nitrite, nitrate, MDA, MPO and TPL levels in the lung lavage samples. Collectively, these findings suggest that 5-ASA is a potent immunomodulator and suppresses key Th2 cytokines production and oxidative stress in OVA-induced asthma.

Clusterin expression level correlates with increased oxidative stress in asthmatics

BackgroundOxidative stress is thought to play a role in the pathogenesis of asthma. Clusterin is a sensitive cellular biosensor of oxidative stress and has antioxidant properties. The function and expression of clusterin in patients with asthma have not been fully investigated. ObjectiveTo investigate whether the expression of clusterin in patients with asthma is regulated by increased oxidative burden and whether clusterin expression could be used to assess the response to inhaled corticosteroids. MethodsClusterin levels in serum, induced sputum, and peripheral blood mononuclear cells of patients with asthma were measured by enzyme-linked immunosorbent assay and western blotting and compared with pulmonary function and levels of expression of hyperoxidized peroxiredoxins. Serum concentrations of clusterin in treatment-naive patients were compared before and after inhaled corticosteroid use. ResultsSerum clusterin concentration was significantly elevated in patients with severe asthma and was inversely correlated with pulmonary function. The expression of hyperoxidized peroxiredoxins was greatly increased in peripheral blood mononuclear cells of patients with asthma and was strongly correlated with clusterin expression. Serum clusterin concentrations in treatment-naive patients with asthma were decreased significantly after initial treatment with inhaled corticosteroids. ConclusionClusterin may be a biomarker of asthma severity and the burden of oxidative stress in patients with asthma. Moreover, clusterin may be useful for the prompt assessment of airway inflammation.

Improving Asthma during Pregnancy with Dietary Antioxidants: The Current Evidence

The complication of asthma during pregnancy is associated with a number of poor outcomes for the mother and fetus. This may be partially driven by increased oxidative stress induced by the combination of asthma and pregnancy. Asthma is a chronic inflammatory disease of the airways associated with systemic inflammation and oxidative stress, which contributes to worsening asthma symptoms. Pregnancy alone also intensifies oxidative stress through the systemic generation of excess reactive oxidative species (ROS). Antioxidants combat the damaging effects of ROS; yet antioxidant defenses are reduced in asthma. Diet and nutrition have been postulated as potential factors to combat the damaging effects of asthma. In particular, dietary antioxidants may play a role in alleviating the heightened oxidative stress in asthma. Although there are some observational and interventional studies that have shown protective effects of antioxidants in asthma, assessment of antioxidants in pregnancy are limited and there are no antioxidant intervention studies in asthmatic pregnancies on asthma outcomes. The aims of this paper are to (i) review the relationships between oxidative stress and dietary antioxidants in adults with asthma and asthma during pregnancy, and (ii) provide the rationale for which dietary management strategies, specifically increased dietary antioxidants, might positively impact maternal asthma outcomes. Improving asthma control through a holistic antioxidant dietary approach might be valuable in reducing asthma exacerbations and improving asthma management during pregnancy, subsequently impacting perinatal health.

Asymmetric Dimethylarginine in Exhaled Breath Condensate and Serum of Children With Asthma

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor and uncoupler of nitric oxide synthase. By promoting the formation of peroxynitrite, ADMA is believed to contribute to several aspects of asthma pathogenesis (ie, airway inflammation, oxidative stress, bronchial hyperresponsiveness, and collagen deposition). The aim of the present study was to compare this mediator in healthy children and children with asthma using the completely noninvasive exhaled breath condensate (EBC) technique. We recruited 77 children with asthma (5-16 years of age) and 65 healthy children (5-15 years of age) who underwent EBC collection and spirometry. Serum ADMA levels and fractional exhaled nitric oxide levels were measured on the same day in a subgroup of children with asthma. EBC was collected using the Turbo-Deccs (Medivac). ADMA levels were measured using the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique. ADMA could be detected in the EBC of 71 subjects with asthma and 64 healthy subjects. ADMA levels in the EBC of children with asthma were significantly higher than in the healthy control subjects (median, 0.12 [interquartile range, 0.05-0.3] vs 0.07 [0.05-0.12]; P = .017), whereas no difference emerged between the children with asthma who were or were not receiving inhaled steroid treatment. No correlation was found between serum and EBC ADMA levels (P &gt; .5). We measured ADMA in EBC by UPLC-MS/MS, a reference analytical technique. Higher ADMA levels were found in children with asthma, supporting a role for this mediator in asthma pathogenesis. This oxidative stress-related mediator also seems to be scarcely affected by steroid therapy. We speculate that ADMA might be a target for new therapeutic strategies designed to control oxidative stress in asthma.

Serum interleukin 27: a possible biomarker of pediatric systemic lupus erythematosus

Background: Asthmatic patients generate reactive oxygen species impairing the antioxidant defense system and creating a state of oxidative stress in asthmatics. Objectives: Determination of the oxidant - antioxidant status in asthmatic children, by measuring the activities of antioxidant enzymes; superoxide dismutases (SOD) and glutathione peroxidases (Gpx) and estimating plasma level of malondialdehyde (MDA) as an index of lipid peroxidation, to find a relation between antioxidant levels and the severity of asthma and the early response to treatment. Methods: This study included 60 children; group (1): 40 asthmatic children and group (2): 20 apparently healthy children as a control group. The following were measured in all the children; plasma level of (MDA), erythrocytes (SOD) and (Gpx) (in asthmatic children two samples were taken; the first during acute attack and the second after 48 hours of treatment). Results: Significant lower erythrocyte antioxidant enzymes activities and higher malondialdehyde was found in asthmatic children compared to the control group, either before or after receiving treatment. In asthmatics, MDA was significantly decreasing and SOD was significantly increasing with treatment. MDA was significantly higher, while SOD was significantly lower with the severity of asthma either before or after receiving treatment. A significant negative correlation was observed between MDA with both of SOD and Gpx, in acute asthmatic attacks. A significant positive correlation was detected between the activities of SOD and Gpx enzymes. Conclusion: Acute asthma leads to a considerable oxidative stress that is indicated by the high level of malondialdehyde and low level of antioxidant enzymes. Keywords: bronchial asthma, superoxide dismutases (SOD), glutathione peroxidases (Gpx), malondialdehyde (MDA), antioxidants Egypt J Pediatr Allergy Immunol 2013;11(1):35-40

Factors Associated with Daily Stress and Asthma Stress in Caregivers of Children with Asthma

Factors Associated with Daily Stress and Asthma Stress in Caregivers of Children with Asthma

Activities of Antioxidant Enzymes in Relation to Oxidative and Nitrosative Challenges in Childhood Asthma

Background. This study aimed to investigate the relationship between antioxidant enzyme activities, extent of airway inflammation, and systemic oxidative stress in children suffering from atopic asthma. Methods. A total of 35 asthmatic (AG) and 21 healthy children (CG) participated in this study. The volume of fractionated exhaled NO (Feno) was measured with the NIOX test system. The activities of the erythrocyte antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and the total antioxidant capacity (TAC) were determined photometrically. Plasma interleukin (IL)-6 was measured using ELISA; malondialdehyde (MDA) levels were analyzed using HPLC. Results. Compared to healthy controls, asthmatic children exhaled a significantly (p < .001) higher mean volume of Feno, had significantly reduced plasma concentrations of TAC (p = .006), and significantly enhanced levels of MDA (p < .001) and IL-6 (p = .012). SOD (p = .027), CAT (p < .001), and GSH-Px (p = .005) were significantly less active in the asthma group and significantly negatively associated with Feno (SOD/Feno: p = .017; CAT/Feno: p = .008; GSH-Px/Feno: p = .001); the oxidative stress marker MDA showed such correlations in both investigated groups (SOD/MDA: AG: p = .001, CG: p = .381; CAT/MDA: AG: p = .003, CG: p = .020; GSH-Px/MDA: AG: p = .006, CG: p = .011). Furthermore, there was a significant (p< .01) positive correlation between MDA/Feno and MDA/IL-6 observed in both groups. Conclusions. These results indicate that inflammation of the bronchial tree, reflected by increased NO formation in the airways and enhanced systemic oxidative stress, is related to an alteration of antioxidant enzyme activities in childhood asthma. Modulating the activity of antioxidant enzymes may therefore have beneficial effects on pulmonary and systemic antioxidant defense mechanisms and could reduce airway inflammation and oxidative stress in asthmatics.

The Possible Role of Clusterin As a Biomarker Representing Increased Oxidative Stress in Asthma

RATIONALE: Asthma is a chronic inflammatory disease and oxidative stress has been known to play an important role in the pathogenesis of asthma. Clusterin, a ubiquitous glycoprotein, is closely linked to various cellular functions to keep homeostasis. Clusterin has been also recognized as a sensitive biosensor responding to increased oxidative stress in other inflammatory diseases. To date, the role of clusterin has not been investigated in asthma.

Oxidative Stress in Asthma

Asthma is a chronic inflammatory lung disease that results in airflow limitation, hyperreactivity, and airway remodeling. There is strong evidence that an imbalance between the reducing and oxidizing systems favoring a more oxidative state is present in asthma. Endogenous and exogenous reactive oxygen species, such as superoxide anion, hydroxyl radical, hypohalite radical, and hydrogen peroxide, and reactive nitrogen species, such as nitric oxide, peroxynitrite, and nitrite, play a major role in the airway inflammation and are determinants of asthma severity. Asthma is also associated with decreased antioxidant defenses, such as superoxide dismutase, catalase, and glutathione. In this review, we will summarize the current knowledge and discuss the current and future strategies for the modulation of oxidative stress in asthma.

The role of oxidative stress in the pathogenesis and treatment of asthma

The role of oxidative stress in asthma is gaining increasing scientific attention. The hallmark of asthma is airway inflammation. Oxidative stress may initiate and augment inflammation, and may also result from inflammation. Exposure to tobacco smoke, ozone, diesel exhaust, and a variety of other pollutants generates reactive oxygen species and other oxidative stressors. Some studies suggest that asthmatics have a decreased ability to respond to oxidative stress, while others find upregulated antioxidative function. Oxidative stress may alter the Th(1)/Th(2) immune response and result in activation of NF-kbeta, a powerful inducer of pro-inflammatory genes. Genetic polymorphisms may play an important role in determining susceptibility to oxidative stress. Many therapeutic strategies to decrease oxidative stress in asthma have been suggested. Dietary changes, antioxidant vitamins, other antioxidant drugs, Ayurvedic supplements, and even radon exposure in a hot bathroom have been studied. Minimizing exposure of young children to environmental tobacco smoke remains paramount.

The Role of Oxidative Stress in the Pathogenesis of Asthma

Oxidative stress plays a critical role in the pathogenesis of asthma. To effectively control oxidative stress in asthmatics, it is important to investigate the precise intracellular mechanism by which the development of immunity, rather than immune tolerance and progression of airway inflammation, is induced. In this article, we suggest that protein tyrosine phosphatases, as intracellular negative regulators, and intracellular antioxidant enzymes such as peroxiredoxins can be regulated by oxidative stress during intracellular signaling.

Pulmonary physiology and pathophysiology in obesity

obesity is now a common occurrence in modern society. Barely one-third of Americans fall into the normal weight range, and 32% of the population has been classified as obese ([9][1]). The obesity epidemic is permeating into the childhood years, with 16.3% of children in the United States being above