Dysfunctional ErbB2, an EGF receptor family member, hinders repair of airway epithelial cells from asthmatic patients

Inoue, Hideki; Hattori, Takeshi; Zhou, Xiaodong; Etling, Emily; Modena, Brian D.; Trudeau, John B.; Holguín, Fernando; Wenzel, Sally E.

doi:10.1016/j.jaci.2018.11.046

Cited by 31 publications

(28 citation statements)

References 48 publications

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“…Notably, TGFBR1 and SMAD3, which mediate TGFβ signalling, are susceptibility loci identified in GWAS for asthma [ 39 ]. ERBB2 mediates epithelial repair processes, and this function may be defective in subjects with asthma and co-opted by type 2 inflammatory processes [ 40 , 41 ]. Together, these data highlight the complexity of the 17q region, which likely contains multiple independent associations with asthma, variations across asthma endotypes and ethnic groups, and functional variations between blood and airway cells.…”

Section: Geneticsmentioning

confidence: 99%

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

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Bosco

2020

IJMS

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Human Respiratory Syncytial Virus and Human Rhinovirus are the most frequent cause of respiratory tract infections in infants and children and are major triggers of acute viral bronchiolitis, wheezing and asthma exacerbations. Here, we will discuss the application of the powerful tools of systems biology to decode the molecular mechanisms that determine risk for infection and subsequent asthma. An important conceptual advance is the understanding that the innate immune system is governed by a Bow-tie architecture, where diverse input signals converge onto a few core pathways (e.g., IRF7), which in turn generate diverse outputs that orchestrate effector and regulatory functions. Molecular profiling studies in children with severe exacerbations of asthma/wheeze have identified two major immunological phenotypes. The IRF7hi phenotype is characterised by robust upregulation of antiviral response networks, and the IRF7lo phenotype is characterised by upregulation of markers of TGFβ signalling and type 2 inflammation. Similar phenotypes have been identified in infants and children with severe viral bronchiolitis. Notably, genome-wide association studies supported by experimental validation have identified key pathways that increase susceptibility to HRV infection (ORMDL3 and CHDR3) and modulate TGFβ signalling (GSDMB, TGFBR1, and SMAD3). Moreover, functional deficiencies in the activation of type I and III interferon responses are already evident at birth in children at risk of developing febrile lower respiratory tract infections and persistent asthma/wheeze, suggesting that the trajectory to asthma begins at birth or in utero. Finally, exposure to microbes and their products reprograms innate immunity and provides protection from the development of allergies and asthma in children, and therefore microbial products are logical candidates for the primary prevention of asthma.

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Section: Geneticsmentioning

confidence: 99%

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

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Bosco

2020

IJMS

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“…Thus could confirm the strong association of JAK2, STAT3 and severe asthma. Erb-B2 tyrosine kinase 2 (ErbB2) was found to be highly correlated with asthma and was suggested to be a novel therapeutic target for asthma [27,28]. Moreover, both NR3C1 and COL1A1 were linked to inflammation in asthmatic airways [29,30].…”

Section: Discussionmentioning

confidence: 99%

Novel Comprehensive Bioinformatics Approaches to Determine the Molecular Genetic Susceptibility Profile of Moderate and Severe Asthma

Zayed

2020

IJMS

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Background: Asthma is a chronic inflammatory condition linked to hyperresponsiveness in the airways. There is currently no cure available for asthma, and therapy choices are limited. Asthma is the result of the interplay between genes and the environment. The exact molecular genetic mechanism of asthma remains elusive. Aims: The aim of this study is to provide a comprehensive, detailed molecular etiology profile for the molecular factors that regulate the severity of asthma and pathogenicity using integrative bioinformatics tools. Methods: The GSE43696 omnibus gene expression dataset, which contains 50 moderate cases, 38 severe cases, and 20 healthy controls, was used to investigate differentially expressed genes (DEGs), susceptible chromosomal loci, gene networks, pathways, gene ontologies, and protein–protein interactions (PPIs) using an intensive bioinformatics pipeline. Results: The PPI network analysis yielded DEGs that contribute to interactions that differ from moderate-to-severe asthma. The combined interaction scores resulted in higher interactions for the genes STAT3, AGO2, COL1A1, CLCN6, and KSR for moderate asthma and JAK2, INSR, ERBB2, NR3C1, and PTK6 for severe asthma. Enrichment analysis (EA) demonstrated differential enrichment between moderate and severe asthma phenotypes; the ion transport regulation pathway was significantly enhanced in severe asthma phenotypes compared to that in moderate asthma phenotypes and involved PER2, GCR, IRS-2, KCNK7, KCNK6, NOX1, and SCN7A. The most enriched common pathway in both moderate and severe asthma is the development of the glucocorticoid receptor (GR) signaling pathway followed by glucocorticoid-mediated inhibition of proinflammatory and proconstrictory signaling in the airway of smooth muscle cell pathways. Gene sets were shared between severe and moderate asthma at 16 chromosome locations, including 17p13.1, 16p11.2, 17q21.31, 1p36, and 19q13.2, while 60 and 48 chromosomal locations were unique for both moderate and severe asthma, respectively. Phylogenetic analysis for DEGs showed that several genes have been intersected in phases of asthma in the same cluster of genes. This could indicate that several asthma-associated genes have a common ancestor and could be linked to the same biological function or gene family, implying the importance of these genes in the pathogenesis of asthma. Conclusion: New genetic risk factors for the development of moderate-to-severe asthma were identified in this study, and these could provide a better understanding of the molecular pathology of asthma and might provide a platform for the treatment of asthma.

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“…Each of those processes is indispensable to achieve airway epithelial repair, and delayed airway repair caused by disrupted repair processes allows external pathogens access to remaining airway tissue, which results in prolonged airway inflammation. In in vitro wound healing models using asthmatic airway epithelial cells, impaired cell proliferation and migration after mechanical wounding was observed and this finding could be a factor for severe asthma phenotype [ 10 , 11 ]. Secondly, “vulnerability to external stimuli” was also observed in asthmatic airway epithelium as shown in impaired tight junction formation [ 8 ].…”

Section: Disrupted Airway Function Of Asthma Epitheliummentioning

confidence: 99%

“…The expression of this gene module was negatively associated with asthma severity, BMI, and exhaled nitric oxide, and positively associated with FEV 1 % predicted and Asthma Quality of Life Questionnaire (AQLQ) scores. The downregulation of ERBB2 in severe asthmatic airway epithelial cells was validated by a following study showing dysregulated ErbB2 phosphorylation in freshly obtained airway epithelial cells from asthmatic patients compared to healthy control group patients [ 10 ]. Functional analysis using the scratch-wound healing model in ALI culture of primary airway epithelial cells was also conducted in this study.…”

Section: Roles Of Epidermal Growth Factor Receptor Family In Asthmmentioning

confidence: 99%

“…Immunocytological staining of phosphorylated ErbB2 showed that phosphorylation of ErbB2 at the leading edge of wounding was downregulated in asthmatic airway epithelial cells compared to control. Applying a specific inhibitor of ErbB2 phosphorylation (mubritinib) to ALI culture induced delayed wound repair in this scratch-wound model [ 10 ].…”

Section: Roles Of Epidermal Growth Factor Receptor Family In Asthmmentioning

confidence: 99%

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Airway Epithelial Dysfunction in Asthma: Relevant to Epidermal Growth Factor Receptors and Airway Epithelial Cells

Inoue

Akimoto

Homma

et al. 2020

JCM

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Airway epithelium plays an important role as the first barrier from external pathogens, including bacteria, viruses, chemical substances, and allergic components. Airway epithelial cells also have pivotal roles as immunological coordinators of defense mechanisms to transfer signals to immunologic cells to eliminate external pathogens from airways. Impaired airway epithelium allows the pathogens to remain in the airway epithelium, which induces aberrant immunological reactions. Dysregulated functions of asthmatic airway epithelium have been reported in terms of impaired wound repair, fragile tight junctions, and excessive proliferation, leading to airway remodeling, which contributes to aberrant airway responses caused by external pathogens. To maintain airway epithelium integrity, a family of epidermal growth factor receptors (EGFR) have pivotal roles in mechanisms of cell growth, proliferation, and differentiation. There are extensive studies focusing on the relation between EGFR and asthma pathophysiology, which describe airway remodeling, airway hypermucus secretion, as well as immunological responses of airway inflammation. Furthermore, the second EGFR family member, erythroblastosis oncogene B2 (ErbB2), has been recognized to be involved with impaired wound recovery and epithelial differentiation in asthmatic airway epithelium. In this review, the roles of the EGFR family in asthmatic airway epithelium are focused on to elucidate the pathogenesis of airway epithelial dysfunction in asthma.

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Dysfunctional ErbB2, an EGF receptor family member, hinders repair of airway epithelial cells from asthmatic patients

Cited by 31 publications

References 48 publications

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

Novel Comprehensive Bioinformatics Approaches to Determine the Molecular Genetic Susceptibility Profile of Moderate and Severe Asthma

Airway Epithelial Dysfunction in Asthma: Relevant to Epidermal Growth Factor Receptors and Airway Epithelial Cells

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