Transcriptional changes in alveolar macrophages from adults with asthma after allergen challenge.
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ABSTRACT:
SUBMITTER: Yang J
PROVIDER: S-EPMC8359176 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In recent years, alveolar macrophages (AM) have been shown to play an important role in environmental allergen-induced airway inflammation in asthma. In this study, we investigated the effect of house dust mite (HDM) and lipopolysaccharide (LPS) challenge on the transcriptome of AM from patients with mild asthma. We have shown previously that intrabronchial HDM/LPS challenge induces a mixed eosinophilic and neutrophil airways inflammation in asthma patients(5). Therefore, we hypothesize that exposure of AM to HDM/LPS would upregulate genes associated with eosinophil and neutrophil signaling. AM were harvested from the bronchoalveolar fluid of 8 asthma patients who were challenged with either saline in one lung segment or HDM/LPS in the contralateral lung segment. We performed RNA sequencing and found over 1000 significantly different expressed genes following HDM/LPS challenge. To the best of our knowledge, this is the first investigation to examine gene expression profiles in AM from asthma patients challenged with HDM and LPS in vivo. Using a well-controlled study design allowing paired analysis of saline and HDM/LPS effects in the same patient, we identified different transcriptional profiles in AM as consequence of local exposure to HDM and LPS. These findings may provide a better understanding of AM functions in (exacerbations of) allergic asthma.
2021-03-16 | GSE144576 | GEO
Project description:Transcriptional changes in alveolar macrophages from adults with asthma after intrabronchial allergen challenge.
| PRJNA604044 | ENA
Project description:Mild asthmatics who met the criteria of the IRB approved protocol of Sub-segmental Bronchial Provocation with Allergen were recruited. The subjects were challenged with sensitive allergen through bronchoscopy. Bronchoalveolar lavage (BAL) fluids were collected before and at 48 hours after allergen challegen. From the BAL fluids, alveolar macrophages were purifed and their RNA was extracted. Total 138 genes including five house keeping genes were evaluated. Two samples of alveolar macrophages from single subject, before and 48 hours after allergen challenge, were directly compared in terms of the expression of inflammatory, chemokine, cytokine genes and their receptor genes.
2014-02-01 | E-GEOD-54585 | biostudies-arrayexpress
Project description:Mild asthmatics who met the criteria of the IRB approved protocol of Sub-segmental Bronchial Provocation with Allergen were recruited. The subjects were challenged with sensitive allergen through bronchoscopy. Bronchoalveolar lavage (BAL) fluids were collected before and at 48 hours after allergen challegen. From the BAL fluids, alveolar macrophages were purifed and their RNA was extracted. Total 138 genes including five house keeping genes were evaluated.
2014-02-01 | GSE54585 | GEO
Project description:Asthma is a complex syndrome associated with episodic decompensations provoked by aeroaller-gen exposures. The underlying pathophysiological states driving exacerbations are latent in the resting state and do not adequately inform biomarker-driven therapy. A better understanding of the pathophysiological pathways driving allergic exacerbations is needed. We hypothesized that disease-associated pathways could be identified in humans by unbiased metabolomics of bron-choalveolar fluid (BALF) during the peak inflammatory response provoked by a bronchial aller-gen challenge. We analyzed BALF metabolites in samples from 12 volunteers who underwent segmental bronchial antigen provocation (SBP-Ag). Metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC–MS/MS) followed by pathway analysis and cor-relation with airway inflammation. SBP-Ag induced statistically significant changes in 549 fea-tures that mapped to 72 uniquely identified metabolites. From these features, two distinct induci-ble metabolic phenotypes were identified by the principal component analysis, partitioning around medoids (PAM) and k-means clustering. Ten index metabolites were identified that in-formed the presence of asthma-relevant pathways, including unsaturated fatty acid produc-tion/metabolism, mitochondrial beta oxidation of unsaturated fatty acid, and bile acid metabolism. Pathways were validated using proteomics in eosinophils. A segmental bronchial allergen chal-lenge induces distinct metabolic responses in humans, providing insight into pathogenic and pro-tective endotypes in allergic asthma.
2022-06-09 | PXD033172 | Pride
Project description:This protocol outlines a single-site mechanistic study aiming to investigate long RNAs differentially expressed in the airway epithelium of asthma patients both at baseline and in response to segmental airway allergen challenges. Over approximately 14 days, the study spanned three visits: Visit 1: Comprehensive characterization of participants, encompassing lung function testing, methacholine challenge testing, and allergen skin prick testing. Visit 2: Participants underwent bronchoscopy wherein three procedures were performed a. Epithelial brushings were performed in a segmental airway (baseline sample) b. Diluent (inactive control) was instilled into another segmental airway c. A small dose of allergen was administered into a third segmental airway using standardized cat or dust mite allergen extracts. Visit 3 (24 hours or 7 days post Visit 2): Another bronchoscopy was carried out to collect epithelial brushings in the diluent challenged and allergen challenged segments The collected epithelial brush samples underwent analysis for mRNA expression in the epithelial brushings. The study successfully incorporated a total of 23 subjects, which included 18 asthmatics (with stable or well-controlled conditions), 2 allergic non-asthmatics, and 3 non-allergic non-asthmatics.
2024-03-08 | GSE250241 | GEO
Project description:BackgroundNasal allergen challenge (NAC) could be a means to assess indication and/or an outcome of allergen-specific therapies, particularly for perennial allergens. NACs are not commonly conducted in children with asthma, and cockroach NACs are not well established. This study's objective was to identify a range of German cockroach extract doses that induce nasal symptoms and to assess the safety of cockroach NAC in children with asthma.MethodsTen adults (18-37 years) followed by 25 children (8-14 years) with well-controlled, persistent asthma and cockroach sensitization underwent NAC with diluent followed by up to 8 escalating doses of cockroach extract (0.00381-11.9 µg/mL Bla g 1). NAC outcome was determined by Total Nasal Symptom Score (TNSS) and/or sneeze score. Cockroach allergen-induced T-cell activation and IL-5 production were measured in peripheral blood mononuclear cells.Results67% (6/9) of adults and 68% (17/25) of children had a positive NAC at a median response dose of 0.120 µg/mL [IQR 0.0380-0.379 µg/mL] of Bla g 1. Additionally, three children responded to diluent alone and did not receive any cockroach extract. Overall, 32% (11/34) were positive with sneezes alone, 15% (5/34) with TNSS alone, and 21% (7/34) with both criteria. At baseline, NAC responders had higher cockroach-specific IgE (P = .03), lower cockroach-specific IgG/IgE ratios (children, P = .002), and increased cockroach-specific IL-5-producing T lymphocytes (P = .045). The NAC was well tolerated.ConclusionWe report the methodology of NAC development for children with persistent asthma and cockroach sensitization. This NAC could be considered a tool to confirm clinically relevant sensitization and to assess responses in therapeutic studies.
| S-EPMC8503840 | biostudies-literature
Project description:GSK256066 is a selective phosphodiesterase 4 inhibitor that can be given by inhalation, minimising the potential for side effects. We evaluated the effects of GSK256066 on airway responses to allergen challenge in mild asthmatics.In a randomised, double blind, cross-over study, 24 steroid naive atopic asthmatics with both early (EAR) and late (LAR) responses to inhaled allergen received inhaled GSK256066 87.5 mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24 h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR.GSK256066 significantly reduced the LAR, attenuating the fall in minimum and weighted mean FEV1 by 26.2% (p = 0.007) and 34.3% (p = 0.005) respectively compared to placebo. GSK256066 significantly reduced the EAR, inhibiting the fall in minimum and weighted mean FEV1 by 40.9% (p = 0.014) and 57.2% (p = 0.014) respectively compared to placebo. There was no effect on pre-allergen FEV1 or methacholine reactivity post allergen. GSK256066 was well tolerated, with low systemic exposure; plasma levels were not measurable after 4 hours in the majority of subjects.GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma.
| S-EPMC2841147 | biostudies-literature
Project description:Purpose: The goal of this study is to investigate the alteration of gene expression pattern of alveolar macrophages by allergen challenge in human asthmatics. Method: By using subsegmental bronchial provocation with allergen (SBP-AG) protocol, we obtained BAL fluids, before and 48 hours after allergen challenge in the subjects enrolled in the protocol. Alveolar macrophages were purified from the BAL fluids and total RNA was isolated. Next-generation sequencing data were generated by using the Illumina system. Results: Using an optimized data analysis workflow, we mapped about 75 million sequence reads per sample to the human genome and identified 29,691 transcripts in the macrophage mRNAs. Among them, the change in the expression profiles of 37 transcripts were statistically significant. Conclusions: It has been well accepted that Th2 cytokine enriched environment transforms the phenotype of macrophages into alternatively activated form. However, the details of a genome-wide gene expression profiles of macrophages were not well investigated. Using RNA-seq technology, we provided comprehensive data of macrophage gene expression profiles in allergic lung inflammation. Our data could offer a framework to study biologic functions of alternatively activated macrophage in chronic inflammatory diseases. mRNA profiles of alveolar macrophages obtained from asthmatics, before and after allergen challenge.
2015-04-01 | E-GEOD-65039 | biostudies-arrayexpress
Project description:Alveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma.We utilized a mechanistic IL-13-driven model and a house dust mite allergen mucosal sensitization model of allergic airway disease to investigate the role of alveolar macrophages in regulating pulmonary inflammation.IL-13-dependent eosinophilic and Th2 inflammation was enhanced in mice depleted of alveolar macrophages using clodronate liposomes. Similarly, depletion of alveolar macrophages during house dust mite sensitization or established disease resulted in augmented Th2 immunity and increased allergen-specific IgG1 and IgE. Clodronate treatment also delayed the resolution of tissue inflammation following cessation of allergen challenge. Strikingly, tissue interstitial macrophages were elevated in alveolar macrophage-deficient mice identifying a new homeostatic relationship between different macrophage subtypes. A novel role for the macrophage-derived immunoregulatory cytokine IL-27 was identified in modulating Th2 inflammation following mucosal allergen exposure.In summary, alveolar macrophages are critical regulators of Th2 immunity and their dysregulation promotes an inflammatory environment with exacerbation of allergen-induced airway pathology. Manipulating IL-27 may provide a novel therapeutic strategy for the treatment of asthma.
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