| 31. |
- Brinkman, Paul, et al.
(författare)
-
Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma
- 2019
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 143:5, s. 1811-1820.e7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes.Objectives: We aimed (1) to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses) and (2) to assess the stability of eNose-derived phenotypes in relation to withinpatient clinical and inflammatory changes.Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability.Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNosedriven clusters (n = 26/33/19) were revealed, showing differences in circulating eosinophil (P = .045) and neutrophil (P = .017) percentages and ratios of patients using oral corticosteroids (P = .035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P = .045).Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.
|
|
| 32. |
- Burg, Dominic, et al.
(författare)
-
Large-Scale Label-Free Quantitative Mapping of the Sputum Proteome
- 2018
-
Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 17:6, s. 2072-2091
-
Tidskriftsartikel (refereegranskat)abstract
- Analysis of induced sputum supematant is a minimally invasive approach to study the epithelial lining fluid and, thereby, provide insight into normal lung biology and the pathobiology of lung diseases. We present here a novel proteomics approach to sputum analysis developed within the U-BIOPRED (unbiased biomarkers predictive of respiratory disease outcomes) international project. We present practical and analytical techniques to optimize the detection of robust biomarkers in proteomic studies. The normal sputum proteome was derived using data-independent HDMSE applied to 40 healthy nonsmoking participants, which provides an essential baseline from which to compare modulation of protein expression in respiratory diseases. The "core" sputum proteome (proteins detected in >= 40% of participants) was composed of 284 proteins, and the extended proteome (proteins detected in >= 3 participants) contained 1666 proteins. Quality control procedures were developed to optimize the accuracy and consistency of measurement of sputum proteins and analyze the distribution of sputum proteins in the healthy population. The analysis showed that quantitation of proteins by HDMSE is influenced by several factors, with some proteins being measured in all participants' samples and with low measurement variance between samples from the same patient. The measurement of some proteins is highly variable between repeat analyses, susceptible to sample processing effects, or difficult to accurately quantify by mass spectrometry. Other proteins show high interindividual variance. We also highlight that the sputum proteome of healthy individuals is related to sputum neutrophil levels, but not gender or allergic sensitization. We illustrate the importance of design and interpretation of disease biomarker studies considering such protein population and technical measurement variance.
|
|
| 33. |
- Dravins, Dainis, et al.
(författare)
-
Spatially resolved spectroscopy across stellar surfaces : II. High-resolution spectra across HD 209458 (G0 V)
- 2017
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 605
-
Tidskriftsartikel (refereegranskat)abstract
- Context. High-resolution spectroscopy across spatially resolved stellar surfaces aims at obtaining spectral-line profiles that are free from rotational broadening; the gradual changes of these profiles from disk center toward the stellar limb reveal properties of atmospheric fine structure, which are possible to model with 3D hydrodynamics. Aims. Previous such studies have only been carried out for the Sun but are now extended to other stars. In this work, profiles of photospheric spectral lines are retrieved across the disk of the planet-hosting star HD 209458 (G0 V). Methods. During exoplanet transit, stellar surface portions successively become hidden and differential spectroscopy provides spectra of small surface segments temporarily hidden behind the planet. The method was elaborated in Paper I, with observable signatures quantitatively predicted from hydrodynamic simulations. Results. From observations of HD 209458 with spectral resolution λ/ Δλ ~ 80 000, photospheric Fe I line profiles are obtained at several center-To-limb positions, reaching adequately high S/N after averaging over numerous similar lines. Conclusions. Retrieved line profiles are compared to synthetic line profiles. Hydrodynamic 3D models predict, and current observations confirm, that photospheric absorption lines become broader and shallower toward the stellar limb, reflecting that horizontal velocities in stellar granulation are greater than vertical velocities. Additional types of 3D signatures will become observable with the highest resolution spectrometers at large telescopes.
|
|
| 34. |
|
|
| 35. |
- George, Leena, et al.
(författare)
-
Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma
- 2020
-
Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : WILEY. - 0105-4538 .- 1398-9995. ; 75:2, s. 370-380
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma.Methods: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/mu L as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values).Results: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts.Conclusion: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.
|
|
| 36. |
- Johansson, Fredrik, 1968-
(författare)
-
Bronchial hyperresponsiveness of ß-adrenoceptor agonists and antagonists in guinea pig airways
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Asthma is one of the most common diseases in the industrialised countries. The underlying mechanisms are complex and still not fully understood although inflammation of the airways plays an important role. There are to day several types of drugs used in the treatment of asthma such as anti-inflammatory drugs, specific antagonists for inflammatory mediators and bronchodilators. Beta-agonists are the main choice for relaxing airway constriction, however unwanted effects of beta-agonists on patients with asthma has been reported. The betaantagonists that are used for treatment of hypertension and various other conditions also is shown to be deleterious in asthmatics. In the present study we have used guinea pig airways to examine the proposed deleterious effects of beta-agonists and antagonists. We have shown that the (S)-enantiomeric forms of salbutamol and formoterol are able to potentiate cholinergic stimuli and we have shown that the potentiation was indomethacin sensitive in airway preparations of sensitised guinea pigs. We also showed and confirmed that the (R)-enantiomeric forms of salbutamol and formoterol were more potent in relaxing airway smooth muscle contracted with different stimuli compared to the (S)-enantiomers. The betaantagonists propranolol and pindolol were shown to be able to contract tracheal preparations if they had been pre-treated with a beta-agonist and the contraction was not simply a blockade of the beta-adrenoceptor induced relaxation. Propranolol contraction was stereo-selective and (S)-propranolol was more effective in inducing contraction than (R)-propranolol. Moreover, atenolol a betacselective antagonist induced significantly smaller contractions compared to general beta-antagonists. This indicates that the beta2-adrenocepor probably is involved in the beta-antagonist induced contraction. The cyclooxygenase inhibitor indomethacin, the 5-lipoxygenase inhibitor MK886 and a thromboxane A2 antagonist as well as capsaicin reduced the beta-antagonist induced contraction. This indicates that several arachidonic acid products as well as neuropeptides may be involved in the beta-antagonistinduced contraction.The worsening of asthma by beta-antagonists is well known and the risks associated with beta-agonists are discussed, but the mechanisms behind these effects need further clarification. In this thesis some of the possible mechanism have been discussed, further studies are needed in order to get more safe and effective asthma treatment regime.
|
|
| 37. |
- Jonasson, Sofia, et al.
(författare)
-
Different effects of deep inspirations on central and peripheral airways in healthy and allergen-challenged mice
- 2008
-
Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9:23
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Deep inspirations (DI) have bronchodilatory and bronchoprotective effects in healthy human subjects, but these effects appear to be absent in asthmatic lungs. We have characterized the effects of DI on lung mechanics during mechanical ventilation in healthy mice and in a murine model of acute and chronic airway inflammation. METHODS: Balb/c mice were sensitized to ovalbumin (OVA) and challenged with nebulized OVA for 1 week or 12 weeks. Control mice were challenged with PBS. Mice were randomly selected to receive DI, which was given twice during the minute before assessment of lung mechanics. RESULTS: DI protected against bronchoconstriction of central airways in healthy mice and in mice with acute airway inflammation, but not when OVA-induced chronic inflammation was present. DI reduced lung resistance induced by methacholine from 3.8+/-0.3 to 2.8+/-0.1 cmH2O*s*mL-1 in healthy mice and 5.1+/-0.3 to 3.5+/-0.3 cmH2O*s*mL-1 in acute airway inflammation (both P < 0.001). In healthy mice, DI reduced the maximum decrease in lung compliance from 15.9+/-1.5% to 5.6+/-0.6% (P < 0.0001). This protective effect was even more pronounced in mice with chronic inflammation where DI attenuated maximum decrease in compliance from 44.1+/-6.6% to 14.3+/-1.3% (P < 0.001). DI largely prevented increased peripheral tissue damping (G) and tissue elastance (H) in both healthy (G and H both P < 0.0001) and chronic allergen-treated animals (G and H both P < 0.0001). CONCLUSIONS: We have tested a mouse model of potential value for defining mechanisms and sites of action of DI in healthy and asthmatic human subjects. Our current results point to potent protective effects of DI on peripheral parts of chronically inflamed murine lungs and that presence of DI may blunt airway hyperreactivity.
|
|
| 38. |
- Konradsen, Jon R, et al.
(författare)
-
Predicting asthma morbidity in children using proposed markers of Th2-type inflammation.
- 2015
-
Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 26:8, s. 772-779
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Assessment of inflammation is becoming a common practice in the clinical work-up of children with persistent asthma. Biomarkers of Th2-mediated inflammation include blood eosinophils (B-Eos), exhaled nitric oxide (FeNO), total serum IgE (S-IgE), and serum periostin. The aim of this study was to investigate the associations between asthma morbidity and increased levels of these biomarkers in pediatric asthma.METHODS: School-age children (n = 96) with various manifestations of persistent asthma were included in this nationwide Swedish study. The protocol included the asthma control test, Juniper's quality of life questionnaire (QoL), assessment of pulmonary function, bronchial hyperresponsiveness, height-adjusted FeNO, blood sampling for S-IgE, B-Eos, and periostin, and high-resolution computed tomography (HRCT) of the lungs.RESULTS: Children with both high levels of height-adjusted FeNO and B-Eos were younger (p = 0.001), had more often severe asthma (p = 0.015), were more allergic (p < 0.001), had a reduced asthma control (p = 0.035), reduced QoL (p = 0.035), more exacerbations (p = 0.004), reduced FEV1/FVC (p = 0.001), and increased bronchial hyperresponsiveness (p < 0.001) as well as greater bronchial wall thickening on HRCT (p = 0.022) compared to those with low levels of both biomarkers. Grouping children according to high and low serum periostin levels did not relate to differences in clinical characteristics and biomarkers.CONCLUSIONS: Assessment of both local and systemic Th2-mediated inflammation by the analysis of easily attainable biomarkers such as exhaled NO and blood eosinophils has a high predictive value for the identification of children with the highest asthma morbidity. Adjusting FeNO values according to the individual child's height increases the clinical usefulness of this biomarker.
|
|
| 39. |
- Krauss-Etschmann, Susanne, et al.
(författare)
-
Of flies, mice and men : a systematic approach to understanding the early life origins of chronic lung disease
- 2013
-
Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 68:4, s. 380-384
-
Forskningsöversikt (refereegranskat)abstract
- Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.
|
|
| 40. |
- Larsson, Britt-Marie, et al.
(författare)
-
Effects of 5-lipoxygenase inhibitor zileuton on airway responses to inhaled swine house dust in healthy subjects
- 2006
-
Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111 .- 1532-3064. ; 100:2, s. 226-37
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inhalation of swine house dust induces acute airway inflammation and increased bronchial responsiveness in healthy subjects. OBJECTIVE: The aim of the study was to investigate whether 5-lipoxygenase products such as leukotrienes may have a role in this reaction. METHODS: Twenty-three healthy subjects were randomised into two groups receiving treatment with either zileuton (600 mg) or placebo four times a day. After 5 days of treatment, all subjects were exposed for 3h in a swine barn. Bronchial responsiveness, exhaled nitric oxide (NO), and mediators in nasal lavage (NAL), blood and urine were measured before and after the exposure. RESULTS: The exposure induced an increased bronchial responsiveness to methacholine in both groups with 2-3 doubling concentration steps, no significant difference between treatments. Leukotriene E(4) in urine increased significantly following exposure in the placebo group from 37.3 (29.1-45.6) (mean (95% confidence interval)) ng/mmol creatinine to 47.7 (36.3-59.0) ng/mmol creatinine (P<0.05), but not in the zileuton group. The post-exposure increase of LTB(4) levels in NAL fluid was totally abolished in the zileuton group (P<0.05 vs. the placebo). The levels of exhaled NO increased significantly (P<0.01), two-fold in both groups. The PGD(2) metabolite 9alpha, 11beta-PGF(2) increased in placebo-treated subjects (P<0.01; P<0.05 vs. zileuton), strengthening mast cell participation. Neutrophil counts and levels of IL-6 in peripheral blood increased in both groups, with a significantly larger increase in zileuton treated subjects (P<0.05 and P<0.001, respectively compared to placebo). CONCLUSIONS: Pre-treatment with clinically recommended doses of the 5-lipoxygenase inhibitor zileuton did not affect the increase of bronchial reactivity induced by swine dust exposure. The intervention totally abolished the LTB(4) release in NAL fluid, but only partially inhibited the formation of leukotrienes as monitored by urinary levels. The enhanced increase of neutrophils and IL-6 in peripheral blood in the zileuton group, suggests that inhibition of 5-lipoxygenase may have pro-inflammatory effects.
|
|
