8 results on '"Dierdorp BS"'
Search Results
2. Metabolic differences between bronchial epithelium from healthy individuals and patients with asthma and the effect of bronchial thermoplasty.
- Author
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Ravi A, Goorsenberg AWM, Dijkhuis A, Dierdorp BS, Dekker T, van Weeghel M, Sabogal Piñeros YS, Shah PL, Ten Hacken NHT, Annema JT, Sterk PJ, Vaz FM, Bonta PI, and Lutter R
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- Adolescent, Adult, Aged, Asthma pathology, Asthma therapy, Female, Gene Expression Profiling, Healthy Volunteers, Humans, Lipid Metabolism genetics, Male, Middle Aged, Oxidative Phosphorylation, Respiratory Mucosa pathology, Severity of Illness Index, Young Adult, Asthma metabolism, Bronchi pathology, Bronchial Thermoplasty, Respiratory Mucosa metabolism
- Abstract
Background: Asthma is a heterogeneous disease with differences in onset, severity, and inflammation. Bronchial epithelial cells (BECs) contribute to asthma pathophysiology., Objective: We determined whether transcriptomes of BECs reflect heterogeneity in inflammation and severity in asthma, and whether this was affected in BECs from patients with severe asthma after their regeneration by bronchial thermoplasty., Methods: RNA sequencing was performed on BECs obtained by bronchoscopy from healthy controls (n = 16), patients with mild asthma (n = 17), patients with moderate asthma (n = 5), and patients with severe asthma (n = 17), as well as on BECs from treated and untreated airways of the latter (also 6 months after bronchial thermoplasty) (n = 23). Lipidome and metabolome analyses were performed on cultured BECs from healthy controls (n = 7); patients with severe asthma (n = 9); and, for comparison, patients with chronic obstructive pulmonary disease (n = 7)., Results: Transcriptome analysis of BECs from patients showed a reduced expression of oxidative phosphorylation (OXPHOS) genes, most profoundly in patients with severe asthma but less profoundly and more heterogeneously in patients with mild asthma. Genes related to fatty acid metabolism were significantly upregulated in asthma. Lipidomics revealed enhanced levels of lipid species (phosphatidylcholines, lysophosphatidylcholines. and bis(monoacylglycerol)phosphate), whereas levels of OXPHOS metabolites were reduced in BECs from patients with severe asthma. BECs from patients with mild asthma characterized by hyperresponsive production of mediators implicated in neutrophilic inflammation had decreased expression of OXPHOS genes compared with that in BECs from patients with mild asthma with normoresponsive production. BECs obtained after thermoplasty had significantly increased expression of OXPHOS genes and decreased expression of fatty acid metabolism genes compared with BECs obtained from untreated airways., Conclusion: BECs in patients with asthma are metabolically different from those in healthy individuals. These differences are linked with inflammation and asthma severity, and they can be reversed by bronchial thermoplasty., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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3. Corticosteroid Withdrawal-Induced Loss of Control in Mild to Moderate Asthma Is Independent of Classic Granulocyte Activation.
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de Groot LES, van de Pol MA, Fens N, Dierdorp BS, Dekker T, Kulik W, Majoor CJ, Hamann J, Sterk PJ, and Lutter R
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- Administration, Inhalation, Adult, Biomarkers analysis, Blood Cell Count, Female, Humans, Male, Oxidative Stress, Prospective Studies, Respiratory Function Tests, Surveys and Questionnaires, Adrenal Cortex Hormones administration & dosage, Asthma drug therapy, Granulocytes drug effects
- Abstract
Background: Loss of asthma control and asthma exacerbations are associated with increased sputum eosinophil counts. However, whether eosinophils, or the also present neutrophils, actively contribute to the accompanying inflammation has not been extensively investigated., Methods: Twenty-three patients with mild to moderate asthma were included in a standardized prospective inhaled corticosteroid (ICS) withdrawal study; 22 of the patients experienced loss of asthma control. The study assessed various immune, inflammatory, and oxidative stress parameters, as well as markers of eosinophil and neutrophil activity, in exhaled breath condensate, plasma, and sputum collected at three phases (baseline, during loss of control, and following recovery)., Results: Loss of asthma control was characterized by increased sputum eosinophils, whereas no differences were detected between the three phases for most inflammatory and oxidative stress responses. There were also no differences detected for markers of activated eosinophils (eosinophil cationic protein and bromotyrosine) and neutrophils (myeloperoxidase and chlorotyrosine). However, free eosinophilic granules and citrullinated histone H
3 , suggestive of eosinophil cytolysis and potentially eosinophil extracellular trap formation, were enhanced. Baseline blood eosinophils and changes in asymmetric dimethylarginine (an inhibitor of nitric oxide synthase) in plasma were found to correlate with the decrease in FEV1 percent predicted upon ICS withdrawal (both, rs = 0.46; P = .03)., Conclusions: The clinical effect in mild to moderate asthma upon interruption of ICS therapy is not related to the classic inflammatory activation of eosinophils and neutrophils. It may, however, reflect another pathway underlying the onset of loss of disease control and asthma exacerbations., Trial Registry: The Netherlands Trial Register; No.: NTR3316; URL: trialregister.nl/trial/3172., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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4. Eosinophils capture viruses, a capacity that is defective in asthma.
- Author
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Sabogal Piñeros YS, Bal SM, Dijkhuis A, Majoor CJ, Dierdorp BS, Dekker T, Hoefsmit EP, Bonta PI, Picavet D, van der Wel NN, Koenderman L, Sterk PJ, Ravanetti L, and Lutter R
- Subjects
- Animals, Antigens, CD metabolism, Antigens, Differentiation, T-Lymphocyte metabolism, Asthma diagnosis, Asthma metabolism, Disease Models, Animal, Eosinophils pathology, Eosinophils ultrastructure, Humans, Influenza A virus physiology, Lectins, C-Type metabolism, Lung immunology, Lung metabolism, Lung pathology, Mice, Mice, Transgenic, Respiratory Function Tests, Asthma etiology, Eosinophils metabolism, Virus Diseases complications, Virus Diseases virology
- Abstract
Background: Activated eosinophils cause major pathology in stable and exacerbating asthma; however, they can also display protective properties like an extracellular antiviral activity. Initial murine studies led us to further explore a potential intracellular antiviral activity by eosinophils., Methods: To follow eosinophil-virus interaction, respiratory syncytial virus (RSV) and influenza virus were labeled with a fluorescent lipophilic dye (DiD). Interactions with eosinophils were visualized by confocal microscopy, electron microscopy, and flow cytometry. Eosinophil activation was assessed by both flow cytometry and ELISA. In a separate study, eosinophils were depleted in asthma patients using anti-IL-5 (mepolizumab), followed by a challenge with rhinovirus-16 (RV16)., Results: DiD-RSV and DiD-influenza rapidly adhered to human eosinophils and were internalized and inactivated (95% in ≤ 2 hours) as reflected by a reduced replication in epithelial cells. The capacity of eosinophils to capture virus was reduced up to 75% with increasing severity of asthma. Eosinophils were activated by virus in vitro and in vivo. In vivo this correlated with virus-induced loss of asthma control., Conclusions: This previously unrecognized and in asthma attenuated antiviral property provides a new perspective to eosinophils in asthma. This is indicative of an imbalance between protective and cytotoxic properties by eosinophils that may underlie asthma exacerbations., (© 2019 The Authors. Allergy Published by John Wiley & Sons Ltd.)
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- 2019
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5. IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity.
- Author
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Ravanetti L, Dijkhuis A, Dekker T, Sabogal Pineros YS, Ravi A, Dierdorp BS, Erjefält JS, Mori M, Pavlidis S, Adcock IM, Rao NL, and Lutter R
- Subjects
- Adaptive Immunity immunology, Animals, Asthma immunology, Cytokines, Humans, Immunity, Innate immunology, Influenza A Virus, H3N2 Subtype, Mice, Mice, Inbred C57BL, Orthomyxoviridae Infections immunology, Pneumonia immunology, Pneumonia virology, Thymic Stromal Lymphopoietin, Asthma virology, Influenza, Human complications, Influenza, Human immunology, Interleukin-33 immunology, Symptom Flare Up
- Abstract
Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive., Objective: We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral activity, and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33-dependent mechanisms that underlie severe asthma exacerbations., Methods: Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti-IL-33 receptor ST2, anti-TSLP, or both., Results: We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite-sensitized mice to dampen IFN-β expression and prevent the T
H 1-promoting dendritic cell phenotype. IL-33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the TH 2 response., Conclusion: Interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy for virus-induced asthma exacerbations., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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6. Anti-IL-5 in Mild Asthma Alters Rhinovirus-induced Macrophage, B-Cell, and Neutrophil Responses (MATERIAL). A Placebo-controlled, Double-Blind Study.
- Author
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Sabogal Piñeros YS, Bal SM, van de Pol MA, Dierdorp BS, Dekker T, Dijkhuis A, Brinkman P, van der Sluijs KF, Zwinderman AH, Majoor CJ, Bonta PI, Ravanetti L, Sterk PJ, and Lutter R
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- Asthma virology, Bronchoalveolar Lavage Fluid cytology, Double-Blind Method, Female, Forced Expiratory Volume, Humans, Interleukin-5 antagonists & inhibitors, Male, Picornaviridae Infections complications, Vital Capacity, Young Adult, Anti-Asthmatic Agents therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Asthma drug therapy, B-Lymphocytes immunology, Macrophages immunology, Neutrophils immunology, Picornaviridae Infections immunology, Rhinovirus immunology
- Abstract
Rationale: Eosinophils drive pathophysiology in stable and exacerbating eosinophilic asthma, and therefore treatment is focused on the reduction of eosinophil numbers. Mepolizumab, a humanized monoclonal antibody that neutralizes IL-5 and efficiently attenuates eosinophils, proved clinically effective in severe eosinophilic asthma but not in mild asthma., Objectives: To study the effect of mepolizumab on virus-induced immune responses in mild asthma., Methods: Patients with mild asthma, steroid-naive and randomized for eosinophil numbers, received 750 mg mepolizumab intravenously in a placebo-controlled double-blind trial, 2 weeks after which patients were challenged with rhinovirus (RV) 16. FEV
1 , FVC, fractional exhaled nitric oxide, symptom scores (asthma control score), viral load (PCR), eosinophil numbers, humoral (luminex, ELISA), and cellular (flow cytometry) immune parameters in blood, BAL fluid, and sputum, before and after mepolizumab and RV16, were assessed., Measurements and Main Results: Mepolizumab attenuated baseline blood eosinophils and their activation, attenuated trendwise sputum eosinophils, and enhanced circulating natural killer cells. Mepolizumab did not affect FEV1 , FVC, and fractional exhaled nitric oxide, neither at baseline nor after RV16. On RV16 challenge mepolizumab did not prevent eosinophil activation but did enhance local B lymphocytes and macrophages and reduce neutrophils and their activation. Mepolizumab also enhanced secretory IgA and reduced tryptase in BAL fluid. Finally, mepolizumab affected particularly RV16-induced macrophage inflammatory protein-3a, vascular endothelial growth factor-A, and IL-1RA production in BAL fluid., Conclusions: Mepolizumab failed to prevent activation of remaining eosinophils and changed RV16-induced immune responses in mild asthma. Although these latter effects likely are caused by attenuated eosinophil numbers, we cannot exclude a role for basophils. Clinical trial registered with www.clinicaltrials.gov (NCT 01520051).- Published
- 2019
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7. An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5-responsive mouse model.
- Author
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Ravanetti L, Dijkhuis A, Sabogal Pineros YS, Bal SM, Dierdorp BS, Dekker T, Logiantara A, Adcock IM, Rao NL, Boon L, Villetti G, Sterk PJ, Facchinetti F, and Lutter R
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- Allergens immunology, Amphiregulin biosynthesis, Animals, Anti-Asthmatic Agents pharmacology, Antibodies, Monoclonal pharmacology, Asthma drug therapy, Biopsy, Cytokines biosynthesis, Disease Models, Animal, Disease Progression, Eosinophils immunology, Eosinophils metabolism, Fluticasone pharmacology, Immunization, Male, Mice, Orthomyxoviridae Infections virology, Pyroglyphidae immunology, Viral Load, Asthma etiology, Asthma pathology, Drug Tolerance, Immunity, Innate, Influenza A virus, Interleukin-5 antagonists & inhibitors, Orthomyxoviridae Infections complications, Steroids pharmacology
- Abstract
Background: Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics., Aim: We developed and characterized a robust, consistent, and reproducible mouse model of severe exacerbation of chronic allergic asthma., Methods: Chronic allergic airway inflammation was induced following a house dust mite (HDM) sensitization protocol. HDM-sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled fluticasone propionate (FP), systemic corticosteroids (Pred), or anti-IL-5. Mice were killed at different time points after infection: Cellular accumulation and cytokines levels in the airways, PenH as a measure of airway hyper-responsiveness (AHR), and lung histology and viral replication were assessed., Results: Infection with low-dose A/X31 H3N2 led to prolonged deterioration of lung function, aggravated mucus production, peri-vascular, peri-bronchial, and allergic inflammation that was unresponsive to inhaled corticosteroids, but responsive to systemic corticosteroids. The exacerbation was preceded at 14 h after virus exposure by a marked innate, but no Th2 and Th1 response subsequently followed by enhanced numbers of eosinophils, neutrophils, dendritic, and T cells into the lung lumen, parenchyma, and draining lymph nodes in HDM-sensitized mice. Anti-IL-5 treatment attenuated eosinophils and prevented the X31-induced exacerbation., Conclusions: Together, these findings indicate that an early innate response that involves eosinophils underlies the exacerbation. This model recapitulates all major features of severe asthma exacerbations and can serve to discern driving mechanisms and promote the development of novel therapeutics., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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8. An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5-responsive mouse model
- Author
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Ravanetti, L, Dijkhuis, A, Sabogal Pineros, YS, Bal, SM, Dierdorp, BS, Dekker, T, Logiantara, A, Adcock, IM, Rao, NL, Boon, L, Villetti, G, Sterk, PJ, Facchinetti, F, Lutter, R, U-BIOPRED Study Group., Other departments, AII - Inflammatory diseases, APH - Global Health, APH - Personalized Medicine, Experimental Immunology, Pulmonology, Medical Research Council (MRC), and Commission of the European Communities
- Subjects
0301 basic medicine ,Male ,Allergy ,Exacerbation ,Biopsy ,RESPIRATORY SYNCYTIAL VIRUS ,DISEASE ,0302 clinical medicine ,INFECTION ,Immunology and Allergy ,Medicine ,Anti-Asthmatic Agents ,innate immunity ,REFRACTORY EOSINOPHILIC ASTHMA ,Sensitization ,biology ,ALLERGIC AIRWAY INFLAMMATION ,Pyroglyphidae ,Antibodies, Monoclonal ,Drug Tolerance ,Viral Load ,respiratory system ,animal models ,medicine.anatomical_structure ,Influenza A virus ,1107 Immunology ,Disease Progression ,Cytokines ,Steroids ,Life Sciences & Biomedicine ,medicine.drug ,Immunology ,virus ,IMMUNITY ,Amphiregulin ,Fluticasone propionate ,Allergic inflammation ,03 medical and health sciences ,Orthomyxoviridae Infections ,Animals ,Asthma ,U-BIOPRED Study Group ,House dust mite ,LUNG-TISSUE ,Innate immune system ,Science & Technology ,business.industry ,MEPOLIZUMAB ,basic immunology ,Allergens ,asthma ,biology.organism_classification ,medicine.disease ,Immunity, Innate ,respiratory tract diseases ,Eosinophils ,Disease Models, Animal ,MICE ,030104 developmental biology ,030228 respiratory system ,CELLS ,Fluticasone ,Immunization ,Interleukin-5 ,business - Abstract
BACKGROUND: Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics. AIM: We developed and characterized a robust, consistent and reproducible mouse model of severe exacerbation of chronic allergic asthma. METHODS: Chronic allergic airway inflammation was induced following a house dust mite (HDM)-sensitization protocol. HDM-sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled Fluticasone Propionate (FP), systemic corticosteroids (Pred) or anti-IL5. Mice were sacrificed at different time points after infection: cellular accumulation and cytokines levels in the airways; PenH as a measure of airway hyperresponsiveness (AHR); lung histology and viral replication were assessed. RESULTS: Infection with low dose A/X31 H3N2 led to prolonged deterioration of lung function, aggravated mucus production, peri-vascular, peri-bronchial and allergic inflammation that was unresponsive to inhaled corticosteroids, but responsive to systemic corticosteroids. The exacerbation was preceded at 14h after virus exposure by a marked innate, but no Th2 and Th1 response, subsequently followed by enhanced numbers of eosinophils, neutrophils, dendritic and T cells into the lung lumen, parenchyma and draining lymph nodes in HDM-sensitized mice. Anti-IL-5 treatment attenuated eosinophils and prevented the X31-induced exacerbation. CONCLUSIONS: Together these findings indicate that an early innate response that involves eosinophils underlies the exacerbation. This model recapitulates all major features of severe asthma exacerbations and can serve to discern driving mechanisms and promote development of novel therapeutics. This article is protected by copyright. All rights reserved.
- Published
- 2017
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