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- Gerhards, R, et al.
(författare)
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Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS
- 2020
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 8:1, s. 207-
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes.
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- Holz, O., et al.
(författare)
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Inflammatory cytokines can be monitored in exhaled breath particles following segmental and inhalation endotoxin challenge in healthy volunteers
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Particles in exhaled air (PEx) are generated when collapsed small airways reopen during breathing. PEx can be noninvasively collected by particle impaction, allowing the analysis of undiluted epithelial lining fluid (ELF). We used the endotoxin (LPS) challenge model to proof the concept that PEx can be used to monitor inflammatory changes in the lung. In this pilot study PEx were collected from ten healthy nonsmoking subjects using the PExA(R) instrument twice before and twice after a segmental LPS challenge (5, 21 h). Following a 4-week washout period, PEx were collected during the week before and 5 h after a whole lung LPS inhalation challenge. PEx biomarkers were compared to blood, bronchoalveolar lavage (BAL) following segmental challenge and induced sputum (ISP) following inhalation challenge. A clear LPS-induced inflammatory response was detectable in BAL fluid, ISP and blood. Albumin and surfactant-protein D were detectable in all PEx samples. While most baseline cytokines were close to or below the detection limit, the median (IQR) IL-6 and IL-8 concentrations in PEx increased significantly after segmental (0.04 (0.03; 0.06) fg/ng PEx; 0.10 (0.08; 0.17) fg/ng PEx) and inhalation LPS challenge (0.19 (0.15; 0.23) fg/ng PEx; 0.32 (0.23; 0.42) fg/ng PEx). Using a highly sensitive analysis platform, we were able to detect a cytokine response in PEx during the early phase of LPS-induced inflammation. This will broaden the spectrum of applications for this noninvasive method to monitor inflammatory processes in the lung, including its use in clinical trials for respiratory drug development. Trial registration: The study has been registered on 07.02.2017 at Clinicaltrials.gov (NCT03044327).
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- Esteve-Codina, Anna, et al.
(författare)
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Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.
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- George, Leena, et al.
(författare)
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Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma
- 2020
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : WILEY. - 0105-4538 .- 1398-9995. ; 75:2, s. 370-380
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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.
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- Larsson, Per, et al.
(författare)
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Exhaled breath particles as a novel tool to study lipid composition of epithelial lining fluid from the distal lung
- 2023
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Ingår i: Bmc Pulmonary Medicine. - 1471-2466. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSurfactant phospholipid (PL) composition plays an important role in lung diseases. We compared the PL composition of non-invasively collected exhaled breath particles (PEx) with bronchoalveolar lavage (BAL) and induced sputum (ISP) at baseline and following endotoxin (LPS) challenges.MethodsPEx and BAL were collected from ten healthy nonsmoking participants before and after segmental LPS challenge. Four weeks later, PEx and ISP were sampled in the week before and after a whole lung LPS inhalation challenge. PL composition was analysed using mass spectrometry.ResultsThe overall PL composition of BAL, ISP and PEx was similar, with PC(32:0) and PC(34:1) representing the largest fractions in all three sample types (baseline PC(32:0) geometric mean mol%: 52.1, 56.9, and 51.7, PC(34:1) mol%: 11.7, 11.9 and 11.4, respectively). Despite this similarity, PEx PL composition was more closely related to BAL than to ISP. For most lipids comparable inter-individual differences in BAL, ISP, and PEx were found. PL composition of PEx was repeatable. The most pronounced increase following segmental LPS challenge was detected for SM(d34:1) in BAL (0.24 to 0.52 mol%) and following inhalation LPS challenge in ISP (0.45 to 0.68 mol%). An increase of SM(d34:1) following segmental LPS challenge was also detectable in PEx (0.099 to 0.103 mol%). The inhalation challenge did not change PL composition of PEx.ConclusionOur data supports the peripheral origin of PEx. The lack of PL changes in PEx after inhalation challenge might to be due to the overall weaker response of inhaled LPS which primarily affects the larger airways. Compared with BAL, which always contains lining fluid from both peripheral lung and central airways, PEx analysis might add value as a selective and non-invasive method to investigate peripheral airway PL composition.Trial registrationNCT03044327, first posted 07/02/2017.
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| 9. |
- Sadiq, Muhammad Waqas, et al.
(författare)
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Lung pharmacokinetics of inhaled and systemic drugs : A clinical evaluation
- 2021
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Ingår i: British Journal of Pharmacology. - : John Wiley & Sons. - 0007-1188 .- 1476-5381. ; 178:22, s. 4440-4451
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung target-site concentrations. We aimed to evaluate lung pharmacokinetics of commonly prescribed drugs by sampling different lung compartments after inhalation and oral administration. Experimental Approach Healthy volunteers received single, sequential doses of either inhaled salbutamol, salmeterol and fluticasone propionate (n = 12), or oral salbutamol and propranolol (n = 6). Each participant underwent bronchoscopies and gave breath samples for analysis of particles in exhaled air at two points after drug administration (1 and 6, 2 and 9, 3 and 12, or 4 and 18 h). Lung samples were taken via bronchosorption, bronchial brush, mucosal biopsy and bronchoalveolar lavage during each bronchoscopy. Blood samples were taken during the 24 h after administration. Pharmacokinetic profiles were generated by combining data from multiple individuals, covering all sample timings. Key Results Pharmacokinetic profiles were obtained for each drug in lung epithelial lining fluid, lung tissue and plasma. Inhalation of salbutamol resulted in approximately 100-fold higher concentrations in lung than in plasma. Salmeterol and fluticasone concentration ratios in lung versus plasma were higher still. Bronchosorption- and bronchoalveolar-lavage-generated profiles of inhaled drugs in epithelial lining fluid were comparable. For orally administered drugs, epithelial-lining-fluid concentrations were overestimated in bronchoalveolar-lavage-generated profiles. Conclusion and Implications Combining pharmacokinetic data derived from several individuals and techniques sampling different lung compartments enabled generation of pharmacokinetic profiles for evaluation of lung targeting after inhaled and oral drug delivery.
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| 10. |
- Watz, Henrik, et al.
(författare)
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Letter to the editor : Indacaterol/glycopyrronium/mometasone furoate compared with salmeterol/fluticasone propionate in patients with asthma: A randomized controlled cross-over study
- 2020
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Indacaterol (IND; 150 μg), glycopyrronium (GLY; 50 μg) and mometasone furoate (MF; 160 μg [high-dose ICS] and 80 μg [medium-dose ICS]) have been formulated as a once-daily (o.d.) fixed-dose combination treatment delivered via the Breezhaler® device for the treatment of patients with asthma. In this randomized (n = 116), double-blind, double-dummy, active comparator-controlled, three-period cross-over study we evaluated the benefit of o.d. IND/GLY/MF versus twice daily (b.i.d.) salmeterol/fluticasone propionate combination (SFC; 50/500 μg; high-dose ICS) treatment (NCT03063086). Overall, 107 patients completed the study. The study met its primary objective by demonstrating superiority of o.d. IND/GLY/MF at medium and high-dose ICS over b.i.d. SFC (high-dose ICS) in peak FEV1 after 21 days of treatment (+ 172 mL with high-dose and + 159 mL with medium-dose IND/GLY/MF versus SFC, p < 0.0001 for each comparison). We also observed that a higher percentage of patients did not need rescue medicine with IND/GLY/MF (high-dose ICS, 58%; medium-dose ICS, 52%) compared with SFC (45%) during the last week of each treatment period. Study treatments were well-tolerated with no relevant differences in tolerability between both IND/GLY/MF doses and SFC. In conclusion, both doses of IND/GLY/MF provided superior lung function benefits compared with twice-daily, standard-of-care SFC at the highest approved dose.
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