8-hydroxy-2--deoxyguanosine and Asthma

Circumstantial evidence suggests that conjugated linoleic acid (CLA) beneficially modulates immune function in allergic subjects. C9,t11-CLA, naturally occurring in ruminant fats, is suggested to be the effective isomer. In contrast, for the t10,c12-CLA isomer, which is naturally found only in traces but usually constitutes a relevant part in commercial CLA mixtures, adverse effects have been reported. Aim of this study was to assess putative immunomodulatory effects of highly enriched c9,t11-CLA in allergic subjects. To our best knowledge, our study is the first in that a CLA preparation was used for such purpose which was free of t10,c12-CLA.. Twenty-nine asthmatic children and adolescents (age 6-18 y) with diagnosed allergic sensitization against grass pollen, house dust mite, or cat hair/epithelia consumed daily a portion of yoghurt containing either 3 g CLA (75 % c9,t11-CLA, 87 % purity) or placebo (safflower oil) over a period of 12 weeks. At study start and end, lung function parameters, specific IgE, in vitro allergen-induced cytokine production in peripheral blood mononuclear cells (PBMC), plasma ECP, urinary 8-oxodG as marker of oxidation, fatty acid profiles of erythrocytes, and routine haematological parameters were determined. Prior to blood samplings, 3-days dietary records were requested. Throughout the study, the participants documented daily their peak expiratory flow and kept protocol about their allergy symptoms and usage of demand medication.. In contrast to the CLA group, PBMC-produced IFN-γ and IL-4 increased significantly and by trend, respectively, in the placebo group. Moreover, plasma ECP tended to increase in the placebo group. In the pollen subgroup, FEV1 improved upon both CLA and placebo oil supplementation. In both intervention groups, the n-6/n-3 PUFA ratio in red blood cells decreased, mainly due to an increase in n-3 PUFA. Moreover, 8-oxodG excretion increased in both groups. No changes occurred regarding specific IgE concentrations, allergy symptoms, and volume parameters.. Our results indicate that CLA modestly dampens the inflammatory response on the cellular level. A clinically relevant amelioration of the symptoms could not be proved in atopic manifest patients.. NCT01026506.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Asthma; Child; Deoxyguanosine; Dietary Supplements; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Interferon-gamma; Interleukin-4; Leukocytes, Mononuclear; Linoleic Acids, Conjugated; Male

To determine the mechanistic roles of oxidative stress, inflammation, and genotoxicity parameters in patients with work-related asthma (WRA) and silicosis.. Thirty-eight healthy office workers, 27 employees with a history of exposure and no disease, 24 employees with WRA, and 23 employees with silicosis were included in this study. Superoxide dismutase, catalase, glutathione peroxidase, malondialdehyde, and interleukins (IL) 17, 23, and 27 levels were measured in the serum. Genotoxic damage was evaluated by calculating the frequency of micronuclei in swab samples and 8-hydroxy-2'-deoxyguanosine in serum.. Serum superoxide dismutase, catalase, glutathione peroxidase, malondialdehyde, 8-hydroxy-2'-deoxyguanosine, and IL-17, IL-23, and IL-27 levels were found to be statistically significantly higher in the exposure, WRA, and silicosis groups compared with the control group. The frequency of micronuclei in buccal epithelial cells of the patient group was found to be significantly higher than that of the control group.. These results may provide information for molecular mechanisms and early diagnosis of WRA and silicosis and will be a guide for taking precautions in the early period.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Asthma; Catalase; DNA Damage; Glutathione Peroxidase; Humans; Malondialdehyde; Oxidative Stress; Silicosis; Superoxide Dismutase

Phthalate exposure is widespread, and studies suggest an adverse relationship with asthma morbidity, including some support for oxidative stress as an underlying pathophysiological mechanism. Urinary phthalate metabolites have been associated with biomarkers of oxidative stress, but data are few in children diagnosed with asthma. We used participant data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine longitudinal relationships between phthalates and oxidative stress in a cohort of Latino children with asthma residing in an agricultural community. We used linear mixed-effects models to estimate associations between 11 urinary phthalate metabolites (and one summed measure of di-2-ethylhexyl phthalate (DEHP) metabolites, ∑DEHP) and two urinary biomarkers of oxidative stress: a biomarker of lipid peroxidation via measure of 8-isoprostane and a biomarker of DNA/RNA oxidative damage via combined measure of 8-hydroxydeoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), and 8-hydroxyguanine. Seventy-nine participants provided 281 observations. In covariate-adjusted models, we observed significant positive relationships between all phthalate metabolites and 8-isoprostane, effect sizes ranging from a 9.3 % (95 % CI: 4.2 %-14.7 %) increase in 8-isoprostane for each 100 % increase (i.e., doubling) of mono-(carboxy-isooctyl) phthalate (MCIOP), to a 21.0 % (95 % CI: 14.3 %-28.2 %) increase in 8-isoprostane for each doubling of mono-n-butyl phthalate (MNBP). For each doubling of mono-(carboxy-isononyl) phthalate (MCINP) and mono-ethyl phthalate (MEP), the DNA/RNA oxidative damage biomarker increased by 6.0 % (95 % CI: 0.2 %-12.2 %) and 6.5 % (95 % CI: 1.4 %-11.9 %), respectively. In conclusion, we provide unique data suggesting phthalate exposure is positively associated with oxidative stress in children with asthma. Our repeat measures provide novel identification of a consistent effect of phthalates on oxidative stress in children with asthma via lipid peroxidation. Confirmation in future studies of children with asthma is needed to enhance understanding of the role of phthalates in childhood asthma morbidity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Agriculture; Asthma; Biomarkers; Child; Diethylhexyl Phthalate; DNA; Environmental Exposure; Environmental Pollutants; Humans; Oxidative Stress; Phthalic Acids; RNA

Volatile organic compounds (VOCs) are important and ubiquitous air pollutants, which may lead to a significant increase in the prevalence of respiratory diseases. To investigate the relationships between VOCs exposure and childhood asthma, 252 asthmatic children and 69 healthy children were recruited. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG, a biomarker of oxidative DNA damage), trans-3'-hydroxycotinine (OH-Cot, a biomarker of passive smoking) and 27 VOC metabolites were simultaneously determined by an ultra-high-performance liquid chromatography-tandem mass spectrometer. Results showed that levels of 8-OHdG and most VOC metabolites in asthmatic children were significantly higher than those in healthy children. More than half of the VOC metabolites were significantly and positively associated with OH-Cot with maximal β coefficient of 0.169, suggesting that second-hand smoking is one important source of VOCs exposure for children in Guangzhou. Significant dose-response relationships between most VOC metabolites and 8-OHdG were observed. Each unit increase in ln-transformed VOC metabolite levels was significantly associated with 5.5-32% increase in ln-transformed 8-OHdG level. Moreover, each unit increase in ln-transformed 8-OHdG level was associated with an 896% increased odd ratios (OR) of asthma in children (OR = 9.96, 95% confidence intervals (CI): 4.75, 20.9), indicating that oxidative stress induced by VOCs exposure may have a significant impact on childhood asthma. Urinary 3-&4-Methylhippuric acid (3-&4-MHA, OR: 5.78, 95% CI: 3.50, 9.54), rac 2-Aminothiazoline-4-carboxylic acid (ATCA, OR: 2.90, 95% CI: 1.69, 4.99) and N-Acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA, OR: 2.76, 95% CI: 1.73, 4.43) which may derive from m/p-xylene, cyanide and 1,3-butadiene exposure, respectively, could significantly and maximally increase the odds of asthma. Interestingly, they also had the strongest associations with 8-OHdG among all investigated VOC metabolites. Moreover, DHBMA strongly correlated with most VOC metabolites. Hence, DHBMA is a suitable biomarker to indicate not only VOCs exposure profile, but also the DNA damage-mediated asthma induced by VOCs.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Asthma; Biological Monitoring; Biomarkers; Child; China; Cotinine; Environmental Pollutants; Female; Humans; Male; Oxidative Stress; Tobacco Smoke Pollution; Volatile Organic Compounds

The global burden of chronic airway diseases represents an important public health concern. The role of oxidative stress and inflammation in the pathogenesis of these diseases is well known. The aim of this study is to evaluate the behavior of both inflammatory and oxidative stress biomarkers in patients with chronic bronchitis, current asthma and past asthma in the frame of a population-based study.. For this purpose, data collected from the Gene Environment Interactions in Respiratory Diseases (GEIRD) Study, an Italian multicentre, multicase-control study, was evaluated. Cases and controls were identified through a two-stage screening process of individuals aged 20-65 years from the general population. Out of 16,569 subjects selected from the general population in the first stage of the survey, 2259 participated in the clinical evaluation. Oxidative stress biomarkers such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), 8-isoprostane and glutathione and inflammatory biomarkers such as Fractional Exhaled Nitric Oxide (FENO) and white blood cells were evaluated in 1878 subjects.. Current asthmatics presented higher levels of FENO (23.05 ppm), leucocytes (6770 n/µL), basophils (30.75 n/µL) and eosinophils (177.80 n/µL), while subjects with chronic bronchitis showed higher levels of GSH (0.29 mg/mL) and lymphocytes (2101.6 n/µL). The multivariable multinomial logistic regression confirmed high levels of leucocytes (RRR = 1.33), basophils (RRR = 1.48), eosinophils (RRR = 2.39), lymphocytes (RRR = 1.26) and FENO (RRR = 1.42) in subjects with current asthma. Subjects with past asthma had a statistically significant higher level of eosinophils (RRR = 1.78) with respect to controls. Subjects with chronic bronchitis were characterized by increased levels of eosinophils (RRR = 2.15), lymphocytes (RRR = 1.58), GSH (RRR = 2.23) and 8-isoprostane (RRR = 1.23).. In our study, current asthmatics show a greater expression of the inflammatory profile compared to subjects who have had asthma in the past and chronic bronchitis. On the other hand, chronic bronchitis subjects showed a higher rate of expression of oxidative stress biomarkers compared to asthmatic subjects. In particular, inflammatory markers such as circulating inflammatory cells and FENO seem to be more specific for current asthma, while oxidative stress biomarkers such as glutathione and 8-isoprostane appear to be more specific and applicable to patients with chronic bronchitis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Asthma; Biomarkers; Bronchitis, Chronic; Case-Control Studies; Dinoprost; Female; Glutathione; Humans; Leukocyte Count; Male; Middle Aged; Oxidative Stress; Young Adult

Adiponectin plays a role in asthma and obesity, but its effects and mechanism in obesity-related asthma remain elusive. This study aimed to evaluate the effects of adiponectin on airway inflammation and oxidative stress and to determine its mechanism in obesity-related asthma. Male C57BL6/J mice fed with a high-fat diet to induce obesity were sensitized and challenged with ovalbumin to induce asthma, and treated with adiponectin (1 mg/kg) and AMP-activated protein kinase (AMPK) inhibitor compound C (20 mg/kg) twice before the first ovalbumin challenge. We found exogenous adiponectin significantly reduced airway resistance, inflammatory infiltration in lung tissue, and cell counts in bronchoalveolar lavage fluid. Adiponectin inhibited great levels of eotaxin, myeloperoxidase, tumor necrosis factor-α, 8‑hydroxy‑2'‑deoxyguanosine, and nitric oxide in obesity-related asthma mice. Moreover, we found increased nuclear factor kappa B p65, inducible nitric oxide synthase and B-cell lymphoma 2 protein expression were down-regulated with adiponectin administration. Additionally, adiponectin elevated the lower levels of pAMPK and AMPK activity in lung tissue. These protective effects of adiponectin were reversed after treatment with the AMPK inhibitor compound C. Thus, we conclude that adiponectin alleviates exacerbation of airway inflammation and oxidative stress in a murine model of obesity-related asthma partly through AMPK signaling pathway.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adiponectin; AMP-Activated Protein Kinases; Animals; Antioxidants; Asthma; Chemokine CCL11; Deoxyguanosine; Immunoglobulin E; Inflammation; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Obesity; Oxidative Stress; Random Allocation

The significance of oxidative stress in pathogenesis of childhood asthma was recognized, but its role in the clinical manifestations of disease is still unclear.. The study was conducted in 96 asthmatic children. The urinary biomarker of oxidative stress, 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG/creatinine) was determined by using HPLC-MS/MS. ELISA was performed to measure myeloperoxidase (MPO) and Cu,Zn- superoxide dismutase (Cu,Zn-SOD) in serum.. Logistic regression analysis revealed that female gender, tobacco smoke exposure, and increased 8-oxodG/creatinine were associated with risk for intermittent asthma, while the positive allergy test and increased Cu,Zn-SOD were associated with eczema in asthmatic children. Higher MPO (p = 0.033), and percent of granulocytes (p = 0.030) were found in severe persistent asthma in comparison to intermittent or mild persistent asthma.. The main findings that TSE-induced oxidative stress is a risk for intermittent asthma and eczema may be clinically significant for the disease prevention and therapeutic improvements.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Asthma; Biomarkers; Child; Child, Preschool; Deoxyguanosine; Eczema; Female; Humans; Male; Oxidative Stress; Peroxidase; Superoxide Dismutase-1; Tobacco Smoke Pollution; Young Adult

In Belgium, around 8.5% of the children have asthmatic symptoms. Increased asthma risk in children has been reported in relation to exposure to phthalate plasticizers but the underlying mechanisms are largely unknown.. The aim of this study was to identify if oxidative stress, assessed by excision of 8-hydroxydeoxyguanosine (8-OHdG) from damaged DNA, is an intermediate marker for the association between phthalate exposure and doctor-diagnosed asthma.. In 418 14-15-year-old youngsters, recruited as a representative sample of residents of Flanders (Belgium), personal exposure to phthalates was assessed by measuring phthalate metabolites in urine: mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-n-butyl phthalate (MnBP), mono-benzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP) and mono-ethyl phthalate (MEP). Analysis of 8-OHdG in urine was used as a sensitive biomarker of oxidative stress at the level of DNA. The presence of doctor-diagnosed asthma was elicited by a self-administered questionnaire. Associations were assessed using multiple linear and logistic regression models. Mediation was tested using Baron and Kenny's regression approach.. A significant increased risk of a youngster being diagnosed with asthma was found for both urinary MnBP (metabolite of dibutyl phthalate (DBP)) and the sum of the three di(2-ethylhexyl) phthalate metabolites (ΣDEHP=MEHP+MEHHP+MEOHP), with respective odds ratio of 1.84 [95% CI: 1.02, 3.32] for MnBP and 1.94 [95% CI: 1.07, 3.51] for ΣDEHP. In addition, we observed significant associations between all urinary phthalate metabolites and increased urinary levels of 8-OHdG. The associations were stronger in girls than in boys. We did not found evidence that 8-OHdG was associated with doctor-diagnosed asthma.. The results of our study are in line with other findings from epidemiological surveys and raise further concern about DEHP and DBP as risk factors for asthma, however, the underlying mechanisms are not yet well understood.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Asthma; Belgium; Deoxyguanosine; Environmental Monitoring; Environmental Pollutants; Female; Humans; Male; Odds Ratio; Oxidative Stress; Phthalic Acids

Prolonged exposure to hyperoxia produces extraordinary amounts of reactive oxygen species (ROS) in the lung and causes hyperoxic lung injury. Although supraphysiological oxygen is routinely administered for the management of respiratory failure, there is no effective strategy to prevent hyperoxic lung injury. In our previous study, we showed that suplatast tosilate, an asthma drug that inhibits T helper 2 (Th2) cytokines, ameliorated bleomycin-induced lung injury and fibrosis through Th2-independent mechanisms. Because bleomycin also generates ROS, we hypothesized that suplatast tosilate might have antioxidant activity and protect the lung against hyperoxic lung injury. To test this hypothesis, mice exposed to hyperoxia were given suplatast tosilate through drinking water. Treatment with suplatast tosilate significantly prolonged mouse survival, reduced the increases in the numbers of inflammatory cells, levels of the pro-inflammatory cytokines/chemokines IL-6 and MCP-1, and protein in bronchoalveolar lavage fluid, and ameliorated lung injury in histological assessment. Suplatast tosilate treatment also significantly inhibited hyperoxia-induced elevations in the levels of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, in bronchoalveolar lavage fluid and 8-isoprostane, a marker of lipid peroxidation, in lung tissue. This finding suggests that suplatast tosilate exerts an antioxidant activity in vivo. In addition, we investigated whether suplatast tosilate has a scavenging effect on hydroxyl radical, the most reactive and harmful ROS, using electron paramagnetic resonance spin-trapping. Suplatast tosilate was shown to scavenge hydroxyl radicals in a dose-dependent manner, and its reaction rate constant with hydroxyl radical was calculated as 2.6×10

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Arylsulfonates; Asthma; Bleomycin; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Deoxyguanosine; DNA Damage; Humans; Hydroxyl Radical; Interleukin-6; Lipid Peroxidation; Lung; Lung Injury; Mice; Oxidative Stress; Reactive Oxygen Species; Sulfonium Compounds; Th2 Cells

To date, no evidence exists in the literature as to the effects of inhaled corticosteroids (ICs) on salivary composition in patients with bronchial asthma.. The aim of this study was to assess the effect of ICs on salival composition.. Adult patients attending an outpatient respiratory clinic who were classified into two groups (controls and patients with bronchial asthma receiving ICs), were recruited in this cross-sectional study. For each participant, data of clinical records, baseline history of asthma, and regular IC dose were recorded. A sample of stimulated saliva was collected and processed for investigation of mucin 5B (MUC5B), lipoxygenase (LPO), total antioxidant capacity, and 8-hydroxydeoxyguanosine (8-OHdG) levels.. Overall, 103 patients (49 controls and 54 patients receiving regular treatment with ICs) were recruited. No differences in comorbidities or smoking habits were observed. Patients treated with high-doses of ICs showed lower levels of salival MUC5B compared with those treated with medium IC doses or those not treated with ICs (1.60 vs. 2.20 vs. 2.53 ng/mL; p = 0.042).. In patients with asthma, treatment with high-doses of ICs is associated with reduced levels of salivary MUC5B. This effect can explain some of the effects of ICs on oral health.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Anti-Asthmatic Agents; Asthma; Cross-Sectional Studies; Deoxyguanosine; Female; Glucocorticoids; Humans; Male; Middle Aged; Saliva

Allergic asthma caused by continuous allergen exposure evokes allergen-specific Th2 responses and is characterized by chronic airway inflammation and hyperresponsiveness. A previous report showed that rebamipide improved asthmatic symptoms in an ovalbumin/trypsin mice model. However, it is still unclear how rebamipide exerts its effects in asthma. In this study, rebamipide improved the asthmatic responses induced by mite exposure in NC/Nga mice, revealing the mechanism of this therapeutic effect. Rebamipide suppressed the infiltration of eosinophils into the airways and lung as well as attenuating the production of reactive oxygen species in tissues. In addition to these anti-inflammatory effects, rebamipide inhibited the production of IL-33, a member of the IL-1 family that drives the subsequent production of Th2-associated cytokines. These observations identify the point where rebamipide exerts its suppressive action on asthma and suggest that rebamipide has therapeutic potential in preventing mite-induced asthma.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine; Allergens; Animals; Antigens, Dermatophagoides; Antioxidants; Asthma; Bronchoalveolar Lavage Fluid; Chemokine CCL11; Chemokine CCL24; Cytokines; Deoxyguanosine; Disease Models, Animal; Interleukin-33; Lung; Macrophages; Male; Mice; Quinolones; Respiratory Hypersensitivity; RNA, Messenger

Lung cytotoxic mechanisms trigger the release of perforin and granzymes, causing oxidative DNA damage that ultimately leads to apoptosis. These effects, although demonstrated in COPD, have not been investigated in patients with asthma and in particular in patients with asthma who smoke. Our aim was to measure perforin, granzyme A, granzyme B, and 8-OHdG expression in sputum from smoking and nonsmoking patients with asthma, compared with smoking and nonsmoking control subjects.. Perforin, granzyme A, granzyme B, and 8-OHdG expression levels were detected by enzyme-linked immunosorbent assays in induced sputum specimens.. Perforin expression was increased in 40% of smokers and 45% of smoking patients with asthma and in only 7% of nonsmoking patients with asthma (P = .004), compared with control subjects' values. In contrast, granzymes A and B levels were increased in > 40% of patients in all three groups vs control subjects. Finally, 8-OHdG levels were elevated in 35% of smoking patients with asthma, in 20% of smokers, and in only 10% of nonsmoking patients with asthma. Statistical analysis revealed a positive correlation between granzyme A (P < .001) and granzyme B (P = .006) expression levels and the number of pack-years in smoking patients with asthma.. Asthma cytotoxic immune response is mainly represented by granzymes A and B, whereas in smoking patients with asthma perforin and 8-OHdG are additionally involved, resembling the immune response in COPD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Asthma; Deoxyguanosine; DNA Damage; Female; Granzymes; Humans; Male; Middle Aged; Oxidation-Reduction; Perforin; Smoking

Asthma is a chronic inflammatory airway disorder associated with recruitment of inflammatory cells. This study aims to clarify the role of oxidative stress and antioxidant status in the deterioration accompanied asthma.. Vitamin E, Vitamin C, superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant status together with the concentrations of lipid peroxides, total nitrates and oxidative DNA damage (8-oxodeoxyguanine) were determined in plasma or whole blood of 47 Saudi asthmatic patients and compared to age-matching control samples.. The present study showed that asthmatic patients have significantly decreased levels of GSH, α-tocopherol, GPx, total antioxidant status and higher levels of SOD, lipid peroxides, total nitrate and 8-oxo-dG. Vitamin C recorded more or less similar levels in both groups.. Alteration of the selected measured parameters confirms that oxidative stress and defective antioxidant status could represent the primary causative factor in the pathogenesis of asthma.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Aged; Aged, 80 and over; alpha-Tocopherol; Antioxidants; Ascorbic Acid; Asthma; Deoxyguanosine; DNA Damage; Female; Glutathione; Humans; Lipid Peroxidation; Lipid Peroxides; Male; Malondialdehyde; Middle Aged; Nitrates; Nitrites; Oxidative Stress; Saudi Arabia; Superoxide Dismutase; Young Adult

Bronchial epithelial injury is the hall mark of asthma which is a chronic airway inflammatory disease. We have shown the mitochondrial ultrastructural changes and dysfunction in bronchial epithelia of OVA induced mice. Reduced L-arginine bioavailability in asthma leads to increased formation of peroxynitrite which could induce mitochondrial dysfunction. We have also shown that L-arginine administration attenuates experimental asthma and reduces peroxynitrite. In this study, we wanted to determine the effect of L-arginine on mitochondrial dysfunction and airway injury in allergic airway inflammation. To determine this, L-arginine was administered to ovalbumin sensitized and challenged mice during allergen challenges. Mitochondrial and cytosolic fractions were purified from the lung to determine key mitochondrial functions, and mitochondrial ultrastructural changes in bronchial epithelia of first generation bronchi were determined. It was found that L-arginine administration increased mitochondrial cytochrome c oxidase activity, reduced cytosolic cytochrome c, increased lung ATP levels, reduced DNA fragmentation in bronchial epithelia and restored the ultrastructural changes of mitochondria of bronchial epithelia. In addition, L-arginine administration reduced the widening of intercellular spaces between adjacent bronchial epithelia. These findings indicated that L-arginine administration reduced airway injury and restored mitochondrial dysfunction in murine allergic airway inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenosine Triphosphate; Animals; Apoptosis; Arginine; Asthma; Bronchi; Cytosol; Deoxyguanosine; Disease Models, Animal; DNA Damage; Electron Transport Complex IV; Immunohistochemistry; In Situ Nick-End Labeling; Lung; Male; Mice; Mice, Inbred BALB C; Mitochondria; Ovalbumin; Respiratory System

Earlier we reported that 7,8-dihydro-8-oxo-deoxyguanosine (8-oxo-dG), an oxidatively modified guanine nucleoside, exerted anti-inflammatory activity through inactivation of the GTP binding protein, Rac. In the present study, the effects of 8-oxo-dG were investigated on responses to antigen challenge in sensitized mice, as Rac is also involved at several steps of the immune process including antigen-induced release of mediators from mast cells.. Mice were sensitized and challenged with ovalbumin without or with oral administration of 8-oxo-dG during the challenge. Effects of 8-oxo-dG were assessed by measuring lung function, cells and cytokines in broncho-alveolar lavage fluid (BALF) and serum levels of antigen-specific IgE. Rac activity in BALF cells was also measured.. 8-oxo-dG inhibited the increased airway resistance and decreased lung compliance of sensitized and challenged mice to the levels of non-sensitized control mice and lowered the increased leukocytes particularly, eosinophils, in BALF. Furthermore, 8-oxo-dG suppressed allergy-associated immune responses, such as raised anti- ovalbumin IgE antibody in serum, increased expression of CD40 and CD40 ligand in lung, increased interleukin-4, -5, -13, interferon-gamma and tumour necrosis factor-alpha in BALF and mRNA levels of these cytokines in BALF cells, dose-dependently. The corresponding purine, 8-oxo-guanine, showed no effects in the same experiments. Finally, 8-oxo-dG, but not 8-oxo-guanine, inhibited the increased Rac activity in sensitized and challenged mice.. 8-Oxo-dG had anti-allergic actions that might be mediated by Rac inactivation. This compound merits further evaluation of its therapeutic potential in allergic asthma.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Anti-Allergic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Deoxyguanosine; Dose-Response Relationship, Drug; Female; Guanine; Immunoglobulin E; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; rac GTP-Binding Proteins; Respiratory Function Tests

In this study we evaluated the effects of the CB1/CB2 cannabinoid receptor agonist CP55, 940 (CP) on antigen-induced asthma-like reaction in sensitized guinea pigs and we tested the ability of the specific CB2 receptor antagonist SR144528 (SR) and CB1 receptor antagonist AM251 (AM) to interfere with the effects of CP. Ovalbumin-sensitized guinea pigs placed in a respiratory chamber were challenged with the antigen given by aerosol. CP (0.4 mg/kg b.wt.) was given i.p. 3 hrs before ovalbumin challenge. Sixty minutes before CP administration, some animals were treated i.p. with either AM, or SR, or both (0.1 mg/kg b.wt.). Respiratory parameters were recorded and quantified. Lung tissue specimens were then taken for histopathological and morphometric analyses and for eosinophilic major basic protein immunohistochemistry. Moreover, myeloperoxidase activity, 8-hydroxy-2-deoxyguanosine, cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) levels, and CB1 and CB2 receptor protein expression by Western blotting were evaluated in lung tissue extracts. In the bronchoalveolar lavage fluid, the levels of prostaglandin D2 and tumour necrosis factor-alpha TNF-alpha were measured. Ovalbumin challenge caused marked abnormalities in the respiratory, morphological and biochemical parameters assayed. Treatment with CP significantly reduced these abnormalities. Pre-treatment with SR, AM or both reverted the protective effects of CP, indicating that both CB1 and CB2 receptors are involved in lung protection. The noted treatments did not change the expression of cannabinoid receptor proteins, as shown by Western blotting. These findings suggest that targeting cannabinoid receptors could be a novel preventative therapeutic strategy in asthmatic patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antigens; Asthma; Camphanes; Cyclic AMP; Cyclohexanols; Deoxyguanosine; DNA Damage; Guinea Pigs; Humans; Leukocytes; Lung; Male; Mast Cells; Models, Biological; Ovalbumin; Piperidines; Prostaglandin D2; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Tumor Necrosis Factor-alpha

Reactive oxygen species have been implicated in the pathogenesis of asthma and, in atopic asthmatics, endogenous superoxide dismutase (SOD) enzyme levels are known to decrease. This suggests that replacing a failed endogenous SOD enzyme system with a mimetic of the endogenous enzyme would be beneficial and protective. In this study we demonstrate that removal of superoxide by the SOD mimetic (SODm) M40403 reduces the respiratory and histopathological lung abnormalities due to ovalbumin (OA) aerosol in a model of allergic asthma-like reaction in sensitized guinea pigs. Both respiratory abnormalities and bronchoconstriction in response to OA challenge are nearly absent in naïve animals, while they sharply became severe in sensitized animals. In addition, OA aerosol induced a reduction of MnSOD activity which was paralleled with bronchiolar lumen reduction, pulmonary air space hyperinflation, mast cell degranulation, eosinophil infiltration, bronchial epithelial cell apoptosis, increase in myeloperoxidase activity, malonyldialdehyde production and 8-hydroxy-2'-deoxyguanosine formation in the lung tissue, as well as elevation of PGD2 in the bronchoalveolar lavage fluid. Treatment with M40403 restored the levels of MnSOD activity and significantly reduced all the above parameters. In summary, our findings support the potential therapeutic use of SOD mimetics in asthma and anaphylactic reactions and account for a critical role for superoxide in acute allergic asthma-like reaction in actively sensitized guinea pig.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Allergens; Animals; Apoptosis; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Deoxyguanosine; Guinea Pigs; Lung; Male; Malondialdehyde; Manganese; Organometallic Compounds; Ovalbumin; Peroxidase; Prostaglandin D2; Superoxide Dismutase