Up-regulation of ACE2, the SARS-CoV-2 Receptor, in Asthmatics on Maintenance Inhaled Corticosteroids
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PROVIDER: PRJNA742421 | ENA |
REPOSITORIES: ENA
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Project description:Background: The first step in SARS-CoV-2 infection is binding of the virus to angiotensin converting enzyme 2 (ACE2) on the airway epithelium. Asthma affects over 300 million people world-wide, many of whom may encounter SARS-CoV-2. Epidemiologic data suggests that asthmatics who get infected may be at increased risk of more severe disease. Our objective was to assess whether maintenance inhaled corticosteroids (ICS), a major treatment for asthma, is associated with airway ACE2 expression in asthmatics. Methods: Large airway epithelium (LAE) of asthmatics treated with maintenance ICS (ICS+), asthmatics not treated with ICS (ICS-), and healthy controls (controls) was analyzed for expression of ACE2 and other coronavirus infection-related genes using microarrays. Results: AsResults: As a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS+ compared to ICS‾ and ACE2 expression was higher in male ICS+ compared to female ICS+ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS- or ICS+. Conclusion: Airway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic. a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS+ compared to ICS‾ and ACE2 expression was higher in male ICS+ compared to female ICS+ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS- or ICS+. Conclusion: Airway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic.
2021-07-15 | GSE179156 | GEO
Project description:The effects of inhaled corticosteroids on healthy airways
| PRJNA1011266 | ENA
Project description:BackgroundThe first step in SARS-CoV-2 infection is binding of the virus to angiotensin converting enzyme 2 (ACE2) on the airway epithelium. Asthma affects over 300 million people world-wide, many of whom may encounter SARS-CoV-2. Epidemiologic data suggests that asthmatics who get infected may be at increased risk of more severe disease. Our objective was to assess whether maintenance inhaled corticosteroids (ICS), a major treatment for asthma, is associated with airway ACE2 expression in asthmatics.MethodsLarge airway epithelium (LAE) of asthmatics treated with maintenance ICS (ICS+), asthmatics not treated with ICS (ICS-), and healthy controls (controls) was analyzed for expression of ACE2 and other coronavirus infection-related genes using microarrays.ResultsAs a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS+ compared to ICS‾ and ACE2 expression was higher in male ICS+ compared to female ICS+ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS- or ICS+.ConclusionAirway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic.
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Project description:The heterogeneity of asthma has prompted attempts at classifications based on clinical phenotypes and cluster designations. Although helpful, reliance on clinical parameters fails to address fundamental issues resulting in specific phenotypes, in particular, steroid-resistant (SR) asthma. Limited data are available defining the mechanisms or pathways (endotypes) causing the failure of inhaled corticosteroids (ICS) in SR asthmatics. Unlike CD4+ T cells, both human and mouse CD8+ T cells fail to undergo apoptosis in the presence of corticosteroids (CS) positioning them as unique effector cells. Whole transcriptome analyses of peripheral CD8+ T cells from steroid-sensitive or steroid-resistant asthmatics or healthy controls on days 0 and 8 were performed.
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Project description:The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. Our objective was to delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS-responsiveness. We performed a randomised open-label bronchoscopy study of high dose ICS therapy in 30 healthy adult volunteers randomised 2:1 to i) fluticasone propionate 500 mcg bd or ii) no treatment (control), for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by bulk RNA sequencing. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B cell immunity (CD20, immunoglobulin heavy and light chains), and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.
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Project description:The Differential Effects of Inhaled Symbicort and AdvaiR on Lung Microbiota (DISARM) study aimed to determine the effects of inhaled corticosteroids (ICS) on the lung microbiome. The full trial protocol is registered at clinicaltrials.gov (NCT02833480) and the study was approved by the Human Research Ethics Committee of the University of British Columbia and Providence Health Care (H14-02277). Participants were randomized to receive inhaled long-acting beta agonist (LABA) treatment with formoterol, or LABA/ICS combination treatment with formoterol/budesonide or salmeterol/fluticasone propionate, for 12 weeks. Bronchoscopy was performed before and after treatment, and bronchoalveolar lavage fluid and bronchial brushes (6th-8th generation) were collected. This dataset contains RNA-seq data from the bronchial brushes. RNA was extracted from cytological brush specimens stored in QIAzol RNA lysis buffer (QIAGEN, Stockach, Germany) using the RNeasy Plus kit (QIAGEN) according to the manufacturer’s instructions, and specimens were submitted for sequencing at the University of British Columbia Biomedical Research Centre. Sample quality control was performed using the Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA). Qualifying samples were then prepared following the standard protocol for the NEBnext Ultra ii Stranded mRNA (New England Biolabs, Ipswich, MA, USA). Sequencing was performed on the Illumina NextSeq 500 (Illumina, San Diego, CA, USA) with paired end 42bp × 42bp reads. Samples were sequenced in batches of 24, with batches formed by random selection of samples.
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Project description:Inhaled allergen challenge of subjects with allergic asthma allows the study of mechanisms involved in allergen-induced airway inflammation. The objective of this study was to identify changes in the plasma proteome associated with a late phase response (LPR) causing airway obstruction occurring 4-8 hours after the initial early response. Serial plasma samples from asthmatics undergoing inhaled allergen challenge were analyzed. Mass spectrometry data was analyzed using a linear regression to model the relationship between the degree of airway obstruction during the LPR and plasma proteome changes evoked by the inhaled allergen challenge. Inhaled allergen challenge induced changes in the plasma proteome including upregulation of the protease inhibitors alpha-1-antitrypsin, alpha-1-antichymotrypsin and plasma serine protease inhibitor. Out of 396 quantified proteins, 150 showed a statistically significant change 23 hours post allergen challenge. Further proteomic changes were associated with the LPR, including altered levels of coagulation factors such as an increased factor XII A and a decreased von Willebrand factor. Allergic reactions to inhaled allergens in asthmatic subjects was associated with changes in a large proportion of the measured plasma proteome, whereof protease inhibitors show the largest changes, likely to influence the inflammatory response. Of several other proteins altered in relation to the LPR, many are associated with coagulation.
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