Bronchial epithelial cell transcriptional responses to inhaled corticosteroids dictate severe asthmatic outcomes

Ginebaugh, Scott P.; Hagner, Matthias; Ray, Anuradha; Erzurum, Serpil C.; Comhair, Suzy; Denlinger, Loren C.; Jarjour, Nizar N.; Castro, Mario; Woodruff, Prescott G.; Christenson, Stephanie A.; Bleecker, Eugene R.; Meyers, Deborah A.; Hastie, Annette T.; Moore, Wendy C.; Mauger, David T.; Israel, Elliot; Levy, Bruce D.; Wenzel, Sally E.; Camiolo, Matthew

doi:10.1016/j.jaci.2023.01.028

Cited by 4 publications

(4 citation statements)

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“…The airway epithelium forms a continuous, highly regulated physical barrier lining the airway lumen, which prevents invasion of inhaled environmental agents. The integrity of the airway epithelial barrier depends on the moderate expression of adhesion molecules in the airway epithelium [ 11 , 12 ]. Adhesion molecules on BECs are involved in the stress response of the airway epithelium, and participate in the maintenance of epithelial structural integrity [1] .…”

Section: Discussionmentioning

confidence: 99%

“…In the presence of environmental pollutants and allergens, the airway epithelium not only acts as an initial barrier but also participates in inflammatory activation. An increasing number of studies have shown that airway epithelial cells play a central role in the pathogenesis of airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD) [ 11 , 12 ]. The denudation of ciliated cells in asthma patients suggests that the airway epithelial barrier is often compromised [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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CTNNAL1 promotes the structural integrity of bronchial epithelial cells through the RhoA/ROCK1 pathway

Liu,

Wang,

Tan

et al. 2024

ABBS

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Adhesion molecules play critical roles in maintaining the structural integrity of the airway epithelium in airways under stress. Previously, we reported that catenin alpha-like 1 (CTNNAL1) is downregulated in an asthma animal model and upregulated at the edge of human bronchial epithelial cells (HBECs) after ozone stress. In this work, we explore the potential role of CTNNAL1 in the structural adhesion of HBECs and its possible mechanism. We construct a CTNNAL1 -/mouse model with CTNNAL1-RNAi recombinant adeno-associated virus (AAV) in the lung and a CTNNAL1-silencing cell line stably transfected with CTNNAL1-siRNA recombinant plasmids. Hematoxylin and eosin (HE) staining reveals that CTNNAL1 -/mice have denuded epithelial cells and structural damage to the airway. Silencing of CTNNAL1 in HBECs inhibits cell proliferation and weakens extracellular matrix adhesion and intercellular adhesion, possibly through the action of the cytoskeleton. We also find that the expressions of the structural adhesion-related molecules E-cadherin, integrin β1, and integrin β4 are significantly decreased in ozone-treated cells than in vector control cells. In addition, our results show that the expression levels of RhoA/ROCK1 are decreased after CTNNAL1 silencing. Treatment with Y27632, a ROCK inhibitor, abolished the expressions of adhesion molecules induced by ozone in CTNNAL1-overexpressing HBECs. Overall, the findings of the present study suggest that CTNNAL1 plays a critical role in maintaining the structural integrity of the airway epithelium under ozone challenge, and is associated with epithelial cytoskeleton dynamics and the expressions of adhesion-related molecules via the RhoA/ROCK1 pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CTNNAL1 promotes the structural integrity of bronchial epithelial cells through the RhoA/ROCK1 pathway

Liu,

Wang,

Tan

et al. 2024

ABBS

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“…An important aim of this study was to provide information on the activity of ICS in healthy airways, to remove the confounding that might occur due to disease‐related changes in gene expression or inherent ICS responsiveness, which should facilitate analyses of gene expression changes in asthma. Studies of severe asthma to‐date 42 have attempted to account for the effects of ICS based on gene expression changes derived from in vitro cell cultures, from an interventional study of gene expression changes in people administered ICS for chronic obstructive pulmonary disease, and from one previous intervention study which used microarrays to assess acute airway transcriptional consequences 6 h after a single inhaled dose of budesonide (1600 μg) in 12 healthy, steroid‐naive men 43 . Our findings are complementary to the previous budesonide study in that some differentially regulated genes are common to our two studies (including upregulation of FKBP5, ZBTB16, PHACTR3 and TSC22D3 and downregulation of CD207, FCER1A and IL33), but there is a striking difference in the overall consequences of a single dose versus 4 weeks twice daily ICS use.…”

Section: Discussionmentioning

confidence: 99%

The effects of inhaled corticosteroids on healthy airways

Marchi,

Hinks,

Richardson

et al. 2024

Allergy

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BackgroundThe effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined.ObjectivesTo 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.MethodsRandomized open‐label bronchoscopy study of high‐dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics.ResultsICS induced small between‐group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. 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.ConclusionsIn 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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“…An important aim of this study was to provide information on the activity of ICS in healthy airways, to remove the confounding that might occur due to disease-related changes in gene expression or inherent ICS responsiveness, which should facilitate analyses of gene expression changes in asthma. Studies of severe asthma to-date (42) have attempted to account for the effects of ICS based on gene expression changes derived from in vitro cell cultures, from an interventional study of gene expression changes in people administered ICS for chronic obstructive pulmonary disease, and from one previous intervention study which used microarrays to assess acute airway transcriptional consequences 6 hours after a single inhaled dose of budesonide (1600 µg) in 12 healthy, steroid-naïve men (43). Our findings are complementary to the previous budesonide study in that some differentially regulated genes are common to our two studies (including upregulation of FKBP5, ZBTB16, PHACTR3, TSC22D3 and downregulation of CD207, FCER1A, IL33), but there is a striking difference in the overall consequences of a single dose versus 4 weeks twice daily ICS use.…”

Section: Discussionmentioning

confidence: 99%

The effects of inhaled corticosteroids on healthy airways

Marchi,

Hinks,

Richardson

et al. 2023

Preprint

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RationaleThe effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined.ObjectivesTo 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.MethodsRandomised 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, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics.Measurements and main resultsICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. 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.ConclusionsIn 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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Bronchial epithelial cell transcriptional responses to inhaled corticosteroids dictate severe asthmatic outcomes

Cited by 4 publications

References 61 publications

CTNNAL1 promotes the structural integrity of bronchial epithelial cells through the RhoA/ROCK1 pathway

CTNNAL1 promotes the structural integrity of bronchial epithelial cells through the RhoA/ROCK1 pathway

The effects of inhaled corticosteroids on healthy airways

The effects of inhaled corticosteroids on healthy airways

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