Studies of exercise-induced bronchoconstriction to define protective mechanisms in asthma

Exercise-induced bronchoconstriction (EIB) occurs in the majority of asthmatics following vigorous exercise. EIB is caused by a loss of water from the airways creating a hyperosmolar environment in the tissue that in turn triggers the release of bronchoconstrictive mediators. These bronchoconstrictive mediators, including histamine, cysteinyl leukotrienes (CysLTs) and prostaglandins, act at their respective receptors on the airway smooth muscle to induce bronchoconstriction. Because the mechanism of EIB involves drying of the airways, provocations mimicking this drying, such as eucapnic voluntary hyperpnea (EVH) and mannitol inhalation can be used to study EIB. With repeated challenge, a smaller response is observed following the second challenge and this decreased responsiveness is called refractoriness. Defining the mechanism of refractoriness may lead to new treatments for asthma. In this thesis a range of airway challenges were performed to study the urinary excretion of mediators released in the lung following EIB and the effect of different interventions. Furthermore, urinary mediator excretion during refractoriness was also studied. For the first time we demonstrated urinary excretion of CysLT and Prostaglandin D2 metabolites after EVH. Mediator release was no different in subjects who did not experience bronchoconstriction following EVH compared to those who did react with bronchoconstriction. This indicates that a necessity of EIB is for the airways to be sensitive to the mediators released. Pre-treatment with the mast cell stabilising drug sodium cromoglycate (SCG) inhibited the airway response to EVH, and the inhibition was accompanied by a decreased release of mediators into the urine. The same effects were observed following pre-treatment with a single high dose of inhaled corticosteroid (ICS). Pre-treatment with fish oil, rich in omega-3 fatty acids, had no effect on the basal excretion of urinary mediators, or airway responsiveness to mannitol challenge. We also report the novel finding of refractoriness following repeated mannitol challenge. Mast cell mediators were excreted into the urine to the same extent after both the first challenge and the repeated challenge 90 min later. Also, those that were most refractory displayed the highest mediator release. This contradicts depletion of mediator release at the time of the second challenge as being the mechanism of refractoriness. These findings were then replicated by repeated EVH challenge. We also demonstrate for the first time an extended spectrum of urinary mediators excreted following EVH. Increased levels of the bronchoprotective mediators PGE2 and PGI2 were seen, which supports the release of protective prostaglandins as being a mechanism of refractoriness. In summary, this thesis provides evidence that the mechanism of refractoriness does not involve mediator depletion. Rather, it indicates that there is a decreased sensitivity at the level of the airway smooth muscle to the mediators released. The induction of this decreased sensitivity may include the release of PGE2 and PGI2, which are likely to mediate protective responses

Urinary leukotriene E4 and prostaglandin D2 metabolites increase in adult and childhood severe asthma characterized by type 2 Inflammation : a clinical observational study

Rationale: New approaches are needed to guide personalized treatment of asthma.Objective: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PG), cysteinyl-leukotrienes (LT) and isoprostanes were quantified in the Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy controls (HC). Validation was performed in 302 SA subjects followed-up after 12-18 months, and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite levels in HC were unrelated to age, BMI and sex, except for the PGE2-pathway. Eicosanoid levels were generally greater in MMA relative to HC, with further elevations in SA, except for PGE2-metabolites in males, which were the same or lower in non-smoking asthmatics as in HC. Metabolite levels were unchanged in asthmatics adherent to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas SA treated with omalizumab had lower levels of LTE4 and the PGD2 metabolite 2,3-dinor-11?-PGF2?. High levels of LTE4 and PGD2-metabolites were associated with lower lung-function, and increased levels of exhaled nitric oxide and eosinophil markers in blood, sputum and urine in U-BIOPRED and in adolescents with asthma. These type-2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study, and found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new non-invasive approach for molecular phenotyping of adult and adolescent asthma

Tjänsteorienterad Integration, ESB

För att dagens system och deras allt mer komplexa applikationer ska kunna integreras med varandra krävs det att de kommunicerar via tjänster. Denna tjänsteorienterade integration uppnås genom att man använder sig av Service Oriented Architecture (SOA) som bygger på löst kopplade tjänster som kommunicerar med varandra på ett standardiserat sätt. En viktig del i en integrationslösning är Enterprise Service Bus (ESB). I denna rapport kommer vi förklara grunderna i tjänsteorienterad integration och sedan fördjupa oss i ESB. Då ESB är ett luddigt begrepp ska vi på ett enkelt och lättbegripligt sätt ge vår syn på begreppet, samt dess fördelar och nackdelar. Vi kommer även att ge marknadens syn på ESB genom en enkätundersökning som innefattar både leverantörer, konsulter och kunder.If today’s software systems and their complex applications shall be able to integrate with each other, they have to communicate through services. This service oriented integration can be accomplished by using Service Oriented Architecture (SOA) where all components are loosely coupled and communicate in a standardized way. An important part when building an integrated solution is the Enterprise Service Bus (ESB). In this report we will explain the basics of SOA and take a more detailed look at the world of ESB. The concept of ESB is not well defined and hence means different things to different people. We are going to present an interpretation of the ESB and its benefits and disadvantages. To find out what the market thinks about ESB we have been talking to producers, consultants and customers

Picosecond excitation for reduction of photolytic effects in two-photon laser-induced fluorescence of CO

Two-photon laser-induced fluorescence for detection of carbon monoxide (CO) frequently shows interferences by emission from photolytically produced C-2 radicals encountered under fuel-rich combustion conditions. Reduced C-2 interference for excitation with laser pulses in the picosecond regime is here demonstrated by comparison with excitation using nanosecond pulses for measurements in laminar premixed ethene-air flames. Compared with nanosecond pulses of 8 ns duration and 4 mJ pulse energy, picosecond pulses of 80 ps duration and around 0.5 mJ pulse energy gave similar to 10 times higher peak power, which allowed for efficient CO excitation and resulted in stronger signal with lower C-2 interference. CO fluorescence with picosecond excitation showed a linear to quadratic power dependence, indicating photoionization, whereas a more quadratic dependence was found for the C-2 interference. A sub-nanosecond effective lifetime of CO resulted in a rapid fluorescence decay compared with C-2 and allowed for efficient reduction in C-2 interference by minimizing the detection gate. In addition, interference compensation using time-resolved detection could be demonstrated. Altogether, picosecond pulses provide efficient two-photon excitation of CO in terms of signal strength as well as reduced C-2 interference. (C) 2012 The Combustion Institute. Published by Elsevier Inc. All rights reserved

The effect of omega-3 fatty acids on bronchial hyperresponsiveness, sputum eosinophilia, and mast cell mediators in asthma.

BACKGROUND: Omega-3 fatty acid supplements have been reported to inhibit exercise-induced bronchoconstriction (EIB). It has not been determined whether omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in people with mild to moderate asthma. METHODS: In a double-blind, crossover trial, subjects with asthma who had BHR to inhaled mannitol (n = 23; 14 men; mean age, 28 years; one-half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0 g/d eicosapentaenoic acid and 2.0 g/d docosahexaenoic acid) or matching placebo for 3 weeks separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) to cause a 15% fall in FEV(1) (PD(15)). Secondary outcomes were sputum eosinophil count, spirometry, Asthma Control Questionnaire (ACQ) score, serum triacylglyceride level, and lipid mediator profile in urine and serum. RESULTS: PD(15) (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119 mg) was not different from placebo (88 mg, 56-139 mg, P = .5). There were no changes in sputum eosinophils (mean ± SD) in a subgroup of 11 subjects (omega-3, 8.4% ± 8.2%; placebo, 7.8% ± 11.8%; P = .9). At the end of each treatment period, there were no differences in FEV(1) % predicted (omega-3, 85% ± 13%; placebo, 84% ± 11%; P = .9) or ACQ score (omega-3, 1.1% ± 0.5%; placebo, 1.1% ± 0.5%; P = .9) (n = 23). Omega-3s caused significant lowering of blood triglyceride levels and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators. CONCLUSIONS: Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophil counts, or inhibit urinary excretion of mast cell mediators in people with mild to moderate asthma, indicating that dietary omega-3 supplementation is not useful in the short-term treatment of asthma. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00526357; URL: www.clinicaltrials.gov

The Effect of Omega-3 Fatty Acids on Bronchial Hyperresponsiveness, Sputum Eosinophilia, and Mast Cell Mediators in Asthma

BACKGROUND: Omega-3 fatty acid supplements have been reported to inhibit exercise-induced bronchoconstriction (EIB). It has not been determined whether omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in people with mild to moderate asthma. METHODS: In a double-blind, crossover trial, subjects with asthma who had BHR to inhaled mannitol (n = 23; 14 men; mean age, 28 years; one-half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0 g/d eicosapentaenoic acid and 2.0 g/d docosahexaenoic acid) or matching placebo for 3 weeks separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) to cause a 15% fall in FEV1 (PD15). Secondary outcomes were sputum eosinophil count, spirometry, Asthma Control Questionnaire (ACQ) score, serum triacylglyceride level, and lipid mediator profile in urine and serum. RESULTS: PD15 (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119 mg) was not different from placebo (88 mg, 56-139 mg, P = .5). There were no changes in sputum eosinophils (mean ± SD) in a subgroup of 11 subjects (omega-3, 8.4% ± 8.2%; placebo, 7.8% ± 11.8%; P = .9). At the end of each treatment period, there were no differences in FEV1 % predicted (omega-3, 85% ± 13%; placebo, 84% ± 11%; P = .9) or ACQ score (omega-3, 1.1% ± 0.5%; placebo, 1.1% ± 0.5%; P = .9) (n = 23). Omega-3s caused significant lowering of blood triglyceride levels and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators. CONCLUSIONS: Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophil counts, or inhibit urinary excretion of mast cell mediators in people with mild to moderate asthma, indicating that dietary omega-3 supplementation is not useful in the short-term treatment of asthma. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00526357; URL: www.clinicaltrials.gov

Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation: A Clinical Observational Study

Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12–18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11β-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma

Urinary Leukotriene E 4 and Prostaglandin D 2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study

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