dinoprost and Bronchial-Hyperreactivity

Exercise-induced bronchoconstriction (EIB) in the asthmatic child is associated with persistent airway inflammation and poor disease control. EIB could arise partly from airway oxidative stress. Exhaled breath condensate (EBC) levels of 8-isoprostane (IsoP), which is a known marker of oxidative stress, might therefore be helpful for monitoring asthma noninvasively.. We recruited 46 asthmatic children and adolescents 6 to 17 years of age (29 boys), all of whom underwent lung function testing, measurement of the fractional concentration of exhaled nitric oxide (FENO), and collection of EBCs for 8-IsoP measurement before and after exercise challenge. FENO was measured before exercise and 5 min and 20 min after exercise. Spirometry was repeated 1, 5, 10, 15, and 20 min after exercise.. Baseline 8-IsoP levels (but not baseline FENO levels) correlated with the fall in FEV(1) 5 min after exercise (r = - 0.47; p = 0.002). 8-IsoP levels measured after exercise remained unchanged from baseline levels; conversely, FENO levels decreased in parallel with the decline in FEV(1) at 5 min (r = 0.44; p = 0.002). The mean baseline 8-IsoP concentrations were higher in patients with EIB (n = 12) than in those without EIB (n = 34; 44.9 pg/mL [95% confidence interval (CI), 38.3 to 51.5] vs 32.3 pg/mL [95% CI, 27.6 to 37.0], respectively; p < 0.01). No difference was found in the mean baseline FENO between groups (with EIB group: 38.7 ppb; 95% CI, 24.5 to 61.1; without EIB group: 29.1 ppb; 95% CI, 22.0 to 38.4).. Increased 8-IsoP concentrations in EBC samples of asthmatic children and adolescents with EIB suggest a role for oxidative stress in bronchial hyperreactivity.

Topics: Adolescent; Asthma; Biomarkers; Breath Tests; Bronchial Hyperreactivity; Child; Constriction, Pathologic; Dinoprost; Exercise; Exhalation; Female; Humans; Male; Oxidative Stress; Reproducibility of Results; Spirometry

The environment in swimming pools, which contain chlorine, might interact with the airway epithelium, resulting in oxidative stress and/or inflammation during high intensity training periods.. We evaluated pulmonary functional (metacholine challenge test, FEV1 and VC), cellular (eosinophils and neutrophils), inflammatory (FeNo, IL-5, IL-6, IL-8 and TNF-α), oxidative (8-isoprostanes) and angiogenesis factors (VEGF) in induced sputum and peripheral blood of 41 healthy non-asthmatic elite swimmers (median 16 years) during the period of high intensity training before a national championship. The second paired sampling was performed seven months later after training had been stopped for one month.. There was a ten-fold increase (median 82-924 pg/ml; P < 0.001) in 8-isoprostanes in induced sputum and five-fold increase (median 82-924 pg/ml; P < 0.001) in sera during training in comparison to the period of rest. However, there was no difference in FEV1 (113 vs 116%), VC (119 vs 118%), FeNo (median 34 vs 38 ppb), eosinophils (2.7 vs 2.9% in sputum; 180 vs 165 cells/μl in blood), neutrophils, different cytokines or VEGF in induced sputum or sera. The only exception was TNF-α, which was moderately increased in sera (median 23 vs 40 pg/ml; P = 0.02) during the peak training period. Almost half (18 of 41) of swimmers showed bronchial hyperresponsiveness during the peak training period (PC20 cutoff was 4 mg/ml). There was no correlation between hyperresponsiveness and the markers of oxidative stress or inflammation.. High intensity training in healthy, non-asthmatic competitive swimmers results in marked oxidative stress at the airway and systemic levels, but does not lead to airway inflammation. However, we could not confirm that oxidative stress is associated with bronchial hyperresponsiveness (AHR), which is often observed during the peak exercise training period.

Topics: Adolescent; Bronchial Hyperreactivity; Bronchial Provocation Tests; Child; Chlorine; Dinoprost; Environmental Exposure; Eosinophils; Female; Humans; Inflammation; Male; Neutrophils; Oxidative Stress; Prospective Studies; Respiratory Function Tests; Sputum; Swimming; Swimming Pools; Teaching; Young Adult

Epidemiological studies suggest that maternal exposure to environmental hazards, such as particulate matter, is associated with increased incidence of asthma in childhood. We hypothesized that maternal exposure to combustion derived ultrafine particles containing persistent free radicals (MCP230) disrupts the development of the infant immune system and results in aberrant immune responses to allergens and enhances asthma severity.. Pregnant C57/BL6 mice received MCP230 or saline by oropharyngeal aspiration on gestational days 10 and 17. Three days after the second administration, blood was collected from MCP230 or saline treated dams and 8-isoprostanes in the serum were measured to assess maternal oxidative stress. Pulmonary T cell populations were assayed in the infant mice at six days, three and six weeks of postnatal age. When the infant mice matured to adults (i.e. six weeks of age), an asthma model was established with ovalbumin (OVA). Airway inflammation, mucus production and airway hyperresponsiveness were then examined.. Maternal exposure to MCP230 induced systemic oxidative stress. The development of pulmonary T helper (Th1/Th2/Th17) and T regulatory (Treg) cells were inhibited in the infant offspring from MCP230-exposed dams. As the offspring matured, the development of Th2 and Treg cells recovered and eventually became equivalent to that of offspring from non-exposed dams. However, Th1 and Th17 cells remained attenuated through 6 weeks of age. Following OVA sensitization and challenge, mice from MCP230-exposed dams exhibited greater airway hyperresponsiveness, eosinophilia and pulmonary Th2 responses compared to offspring from non-exposed dams.. Our data suggest that maternal exposure to MCP230 enhances postnatal asthma development in mice, which might be related to the inhibition of pulmonary Th1 maturation and systemic oxidative stress in the dams.

Topics: Age Factors; Animals; Asthma; Bronchial Hyperreactivity; Cytokines; Dinoprost; Female; Gestational Age; Inflammation Mediators; Inhalation Exposure; Lung; Maternal Exposure; Mice, Inbred C57BL; Ovalbumin; Oxidative Stress; Particulate Matter; Pregnancy; Prenatal Exposure Delayed Effects; Pulmonary Eosinophilia; Severity of Illness Index; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Th2 Cells

One host susceptibility factor for ozone identified in epidemiologic studies is NAD(P)H quinone oxidoreductase 1 (NQO1). We hypothesized that after ozone exposure, NQO1 is required to increase 8-isoprostane (also known as F(2)-isoprostane) production, a recognized marker of ozone-induced oxidative stress, and to enhance airway inflammation and hyperresponsiveness. In this report, we demonstrate that in contrast to wild-type mice, NQO1-null mice are resistant to ozone and have blunted responses, including decreased production of F(2)-isoprostane and keratinocyte chemokine, decreased airway inflammation, and diminished airway hyperresponsiveness. Importantly, these results in mice correlate with in vitro findings in humans. In primary human airway epithelial cells, inhibition of NQO1 by dicumarol blocks ozone-induced F(2)-isoprostane production and IL-8 gene expression. Together, these results demonstrate that NQO1 modulates cellular redox status and influences the biologic and physiologic effects of ozone.

Topics: Animals; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cells, Cultured; Chemokines; Dicumarol; Dinoprost; Enzyme Inhibitors; Epithelial Cells; Humans; Interleukin-8; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone); NADPH Dehydrogenase; Oxidants; Oxidation-Reduction; Oxidative Stress; Ozone; Pneumonia; Time Factors

The effective microorganism fermentation extract (EM-X) is an antioxidant cocktail derived from the fermentation of plant material with effective microorganisms, and its clinical application is being increasingly scrutinized. In the current study, the antiasthmatic effect of EM-X was investigated using a mouse model. Inhalation of EM-X during OVA challenge resulted in a significant reduction in airway hyperreactivity (AHR) and airway recruitment of leukocytes including eosinophils. However, the level of 8-isoprostane in bronchoalveolar lavage fluid (BALF), a marker of oxidative stress in asthmatic patients, was unaltered by EM-X inhalation. Instead, ELISA data showed that levels of IL-4, IL-5 and IL-13 in BALF or lung tissues were significantly lower in EM-X-inhaling mice than in the control mice, but not the IFN-gamma level. A considerably lower amount of Ag-specific IgE and IgG1 was detected in the serum of EM-X-inhaling mice than in the serum of the controls, whereas their IgG2a secretion was similar. In addition, Ag-specific ex vivo IL-4, IL-5 and IL-13 production of draining lymph node cells was markedly diminished by EM-X inhalation, but not IFN-gamma. These data clearly show that inhaled EM-X suppresses type 2 helper T (TH2), but not type 1 helper T (TH1), response. In conclusion, inhalation of EM-X attenuates AHR and airway inflammation which results from selective inhibition of the TH2 response to allergen, but independently of antioxidant activity. Our data also suggest that EM-X may be effectively applied for control of allergic asthma.

Topics: Administration, Inhalation; Animals; Anti-Asthmatic Agents; Antigens; Antioxidants; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Dinoprost; Disease Models, Animal; Female; Immunoglobulins; Inflammation; Lung; Lymph Nodes; Mice; Mice, Inbred BALB C; Plant Extracts; Th2 Cells

We investigated the role of antioxidants in airway hyperresponsiveness to acetylcholine using young asthma model mice, which were sensitized and stimulated with ovalbumin.. The mice had been fed either a normal diet, an alpha-tocopherol-supplemented diet or a probucol-supplemented diet 14 days before the first sensitization. They were immunized with antigen at intervals of 12 days and, starting from 10 days after the second immunization, they were exposed to antigen 3 times every 4th day using an ultrasonic nebulizer. Twenty-four hours after the last antigen inhalation, airway responsiveness to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was collected. A blood and lung tissue study was also carried out.. Twenty-four hours after the last antigen challenge, both IL-4 and IL-5 in the BALF of alpha-tocopherol-supplemented mice were significantly decreased. The IL-5 level in probucol-supplemented mice was also decreased, but there was no difference in IL-4 levels. The serum IgE level was decreased in probucol-supplemented mice. Differential cell rates of the fluid revealed a significant decrease in eosinophils due to antioxidant supplementation. Airway hyperresponsiveness to acetylcholine was also repressed in antioxidant-supplemented mice. In histological sections of lung tissue, inflammatory cells and mucus secretion were markedly reduced in antioxidant-supplemented mice. We investigated the antioxidant effect on our model mice by examining 8-isoprostane in BALF and lung tissue, and acrolein in BALF; however, our experiment gave us no evidence of the antioxidant properties of either alpha-tocopherol or probucol contributing to the reduction of airway inflammation.. These findings indicate that alpha-tocopherol and probucol suppress allergic responses in asthma model mice, although these two drugs cause suppression in different ways that are unrelated to antioxidation.

Topics: Acrolein; Allergens; alpha-Tocopherol; Animals; Antioxidants; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Dietary Supplements; Dinoprost; Disease Models, Animal; Eosinophils; Female; Hypersensitivity; Immunoglobulin E; Interleukin-4; Interleukin-5; Mice; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Probucol

This study investigated the capacity of conjugated linoleic acids (CLA) to reduce ex vivo antigen-induced release of eicosanoids in a type I hypersensitivity model. Guinea pigs were fed a diet containing 0.25% safflower oil (control) or 0.25% CLA [43% trans (t)10, cis (c)12; 41% c9, t11/t9, c11 18:2] for 2 wk before and during sensitization to ovalbumin (OVA). Lungs, tracheas, and bladders were incubated in physiological saline solution (PSS) for 1 h (basal mediator release) and challenged with OVA (0.01 g/l PSS) for 1 h (mediator release in response to antigen). Eicosanoids were quantified by HPLC/tandem mass spectrometry or enzyme immunoassay. CLA feeding resulted in no change in basal release but decreased eicosanoid release from sensitized tissues in response to antigen challenge in the following manner: thromboxane B(2), 6-keto-prostaglandin (PG)F(1alpha), PGF(2alpha), PGD(2), PGE(2) by 57-75% in lung, 45-65% in trachea, and 38-60% in bladder; and leukotriene C(4)/D(4)/E(4) by 87, 90, and 50% in lung, trachea, and bladder, respectively. These data indicate that feeding CLA reduces lipid-derived inflammatory mediators produced by this type I hypersensitivity model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blotting, Western; Bronchial Hyperreactivity; Cyclooxygenase 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Guinea Pigs; Hypersensitivity, Immediate; Isoenzymes; Linoleic Acid; Ovalbumin; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Trachea; Urinary Bladder

Prior airway exposure to wood smoke induces an increase in airway responsiveness to subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998; 66: 971, 2000). To further characterize this airway hyperreactivity, we investigated and compared the airway responsiveness to bronchoconstrictor challenge before and 30 min after sham air exposure or wood smoke exposure in anesthetized and artificially ventilated guinea pigs. Various doses of substance P (0.8-6.4 microg/kg), capsaicin (0.2-3.2 microg/kg), prostaglandin F2alpha (30-3000 microg/kg), histamine (1-8 microg/kg), or acetylcholine (5-20 microg/kg) were intravenously injected at 2-min intervals in successively increasing doses to obtain the dose required to provoke a 200% increase in baseline total lung resistance (ED200). Wood smoke exposure significantly lowered the ED200 of substance P, capsaicin, and prostaglandin F2alpha whereas sham air exposure failed to do so. Furthermore, wood smoke exposure did not significantly alter the ED200 of histamine or acetylcholine. Pretreatment with phosphoramidon (2 mg/kg), an inhibitor of the neutral endopeptidase (the major degradation enzyme of substance P), before smoke exposure did not significantly affect the smoke-induced reduction in ED200 of substance P. Sectioning both cervical vagi before smoke exposure did not significantly alter the smoke-induced reduction in ED200 of capsaicin or prostaglandin F2alpha. These results suggest that airway exposure to wood smoke acutely produces airway hyperresponsiveness to substance P, capsaicin, and prostaglandin F2alpha, but not to histamine or acetylcholine. Since the combination of phosphoramidon and wood smoke exposure did not result in an additive potentiation of smoke-induced airway hyperresponsiveness to substance P, it is suggested that an inhibition of the degradation enzyme of substance P may contribute to this increase in airway reactivity. Furthermore, vagally-mediated bronchoconstriction does not play a vital role in enhanced airway responsiveness to capsaicin or prostaglandin F2alpha.

Topics: Acetylcholine; Airway Resistance; Animals; Blood Pressure; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Capsaicin; Dinoprost; Guinea Pigs; Histamine; Injections, Intravenous; Lung; Male; Respiratory Mechanics; Smoke; Substance P; Wood

We studied the effect of intravenous administration of 13,14-dihydro-15-keto-prostaglandin (PG) F2 alpha on airway responsiveness to histamine and airway wall thickening in guinea-pigs. Guinea-pigs were killed and the lungs were fixed in formalin. Slides from paraffin-embedded sections of the lungs were stained and the airways that were cut in transverse section were measured by tracing enlarged images using a digitizer. Moreover, airway resistance (Raw) was determined by a pulmonary mechanics analyser and we calculated two indices, an index of airway wall thickening and the one of airway hyperresponsiveness to histamine, from changes of baseline-Raw and peak-Raw following intravenous administration of histamine before and after the intravenous administration of 13,14-dihydro-15-keto-PGF2 alpha. Intravenous administration of 10 micrograms/kg 13,14-dihydro-15-keto-PGF2 alpha for 1 h did not induce an increase of the relative thickness of the airway wall by the histological examination. In analysis of airway function, intravenous administration of 10 micrograms/kg 13,14-dihydro-15-keto-PGF2 alpha for 1 h induced airway hyperresponsiveness to histamine without airway wall thickening. Thromboxane A2 (TXA2) receptor antagonists ONO-NT-126 and ONO-8809 inhibited the 13,14-dihydro-15-keto-PGF2 alpha-induced airway hyperresponsiveness to histamine, suggesting that the effect of 13,14-dihydro-15-keto-PGF2 alpha on bronchial hyperresponsiveness is likely to be mediated through TXA2.

Topics: Animals; Bridged Bicyclo Compounds; Bronchi; Bronchial Hyperreactivity; Bronchoconstriction; Dinoprost; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Infusions, Intravenous; Male; Thromboxane A2

Prostaglandin F2 alpha (PGF2 alpha) has been suggested to play a role in the pathogenesis of bronchial asthma. In this study, the effects of intravenous administration of 13,14-dihydro-15-keto-PGF2 alpha, a stable metabolite of PGF2 alpha, on bronchial smooth muscle in guinea pigs were investigated by measuring dynamic respiratory resistance using a formula that excludes the effects of differences in airway wall thickness. With this formula, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness. Administration of 13,14-dihydro-15-keto-PGF2 alpha did not induce airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was significantly enhanced by the administration of 13,14-dihydro-15-keto-PGF2 alpha. Moreover, TXA2 antagonists, ONO-NT-126 and ONO-8809, inhibited the effect of 13,14-dihydro-15-keto-PGF2 alpha administration. These results suggest that 13,14-dihydro-15-keto-PGF2 alpha can be important mediators affecting bronchial hyperresponsiveness, and TXA2 may play a part in the 13,14-dihydro-15-keto-PGF2 alpha-induced bronchial hyperresponsiveness.

Topics: Administration, Oral; Animals; Bridged Bicyclo Compounds; Bronchi; Bronchial Hyperreactivity; Bronchoconstriction; Dinoprost; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Injections, Intravenous; Male; Thromboxane A2

We studied the effect of intravenous administration of 9 alpha,11 beta-prostaglandin F2 on bronchial responsiveness to histamine and airway wall thickening in guinea pigs. The infusion of 9 alpha,11 beta-prostaglandin F2 induced an increase of the relative thickness of the airway wall in peripheral bronchi demonstrable by histological examination. Analysis of airway function showed that the infusion of 9 alpha,11 beta-prostaglandin F2 induced airway hyperresponsiveness to histamine with airway wall thickening. The thromboxane A2 receptor antagonists, ONO-NT-126 (5(Z)-6-[(1R,2R,3R,4S)-3-(n-4-bromobenzenesulfonyl-aminomethyl) bicyclo[2.2.1]heptane-2-yl]hex-5-enoic acid) and ONO-8809 (n-decyl(Z)-6-[(1S,2S,3R,4R)-3-(4-bromobenzenesulfonylaminomethyl) bicyclo[2.2.1]hept-2-yl]-5-hexenoate), inhibited these effects of 9 alpha,11 beta-prostaglandin F2 in a dose-dependent manner.

Topics: Airway Resistance; Animals; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Dinoprost; Dose-Response Relationship, Drug; Drug Interactions; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Infusions, Intravenous; Male; Muscle Contraction; Muscle, Smooth; Receptors, Thromboxane

The effects of intravenous administration of 9 alpha,11 beta-PGF2, a stable metabolite of prostaglandin D2 (PGD2), on bronchial smooth muscle in guinea pigs were investigated by measurement of dynamic compliance and dynamic respiratory resistance using a formula to exclude the effects of differences in airway wall thickness. With this formula, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness to histamine. Administration of 9 alpha,11 beta-PGF2 induced airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was significantly enhanced by the administration of 9 alpha,11 beta-PGF2a. TXA2 antagonists, ONO-NT-128 and ONO-8809, inhibited the effect of 9 alpha,11 beta-PGF2 administration. These results suggest that 9 alpha,11 beta-PGF2 act as important mediators affecting bronchial hyperresponsiveness, and TXA2 may play a role in 9 alpha,11 beta-PGF2-induced airway wall edema and bronchial hyperresponsiveness to histamine.

Topics: Animals; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Dinoprost; Guinea Pigs; Histamine; Injections, Intravenous; Male; Thromboxane A2