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- Kolmert, Johan, et al.
(författare)
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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
- 2021
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - NEW YORK, USA : AMER THORACIC SOC. - 1073-449X .- 1535-4970. ; 203:1, s. 37-53
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Tidskriftsartikel (refereegranskat)abstract
- 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 PGE(2) pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE(2) 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 PGD(2) metabolite 2,3-dinor-11 beta-PGF(2 alpha). High concentrations of LTE4 and PGD(2) metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOARED 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.
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| 2. |
- Bood, Johan
(författare)
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Studies of exercise-induced bronchoconstriction to define protective mechanisms in asthma
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 3. |
- Brackmann, Christian, et al.
(författare)
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Picosecond excitation for reduction of photolytic effects in two-photon laser-induced fluorescence of CO
- 2013
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Ingår i: Proceedings of the Combustion Institute. - : Elsevier BV. - 1540-7489. ; 34, s. 3541-3548
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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