Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model

El-Hashim, Ahmed Z.; Khajah, Maitham A.; Renno, Waleed M.; Babyson, Rhema S.; Uddin, Mohib; Benter, İbrahim F.; Ezeamuzie, Charles I.; Akhtar, Saghir

doi:10.1038/s41598-017-09349-0

Cited by 62 publications

(78 citation statements)

References 56 publications

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“…Arrows point to the regions of interest referred to in the Results sections airways inflammation. 55 Our novel finding that ERBB3 is up-regulated in severe asthma requires further investigation as it suggests that EGFR/ ERBB3 heterodimers may contribute to corticosteroid-refractory asthma. As EGFR and corticosteroids also have beneficial effects on epithelial repair and barrier function, 54 discriminating between pro-inflammatory and pro-repair functions for these pathways, and the role(s) of individual ligands and ERBB receptor heterodimers, should help to tailor more effective therapies for severe asthma.…”

Section: Discussionmentioning

confidence: 92%

“…53 We have previously shown that EGFR protein expression is increased in the bronchial epithelium of asthmatic patients according to disease severity 54 ; furthermore, EGFR expression correlates with epithelial IL-8 levels and the extent of neutrophilic inflammation in severe asthma. 33,34 Although involvement of the EGFR in inflammatory responses has been demonstrated previously using murine models of ovalbumin 55 or house dust mite-induced allergic inflammation, 56,57 both of these models are corticosteroid sensitive and so cannot address those corticosteroid-refractory responses that are important in severe asthma. Using the IL-13 transgenic mouse model, we identified a subset of IL-13-driven F I G U R E 4 The Type 2 lung inflammation signature is reduced by dexamethasone, but not the proneutrophilic responses.…”

Section: Discussionmentioning

confidence: 99%

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Involvement of the epidermal growth factor receptor in IL‐13–mediated corticosteroid‐resistant airway inflammation

Davies

Perotin-Collard

Kelly

et al. 2020

Clin Experimental Allergy

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Background: Effective treatment for severe asthma is a significant unmet need. While eosinophilic inflammation caused by Type 2 cytokines is responsive to corticosteroid and biologic therapies, many severe asthmatics exhibit corticosteroid-unresponsive mixed granulocytic inflammation.Objective: Here, we tested the hypothesis that the pro-allergic cytokine, IL-13, can drive both corticosteroid-sensitive and corticosteroid-resistant responses.Results: By integration of in vivo and in vitro models of IL-13-driven inflammation, we identify a role for the epidermal growth factor receptor (EGFR/ERBB1) as a mediator of corticosteroid-unresponsive inflammation and bronchial hyperresponsiveness driven by IL-13. Topological data analysis using human epithelial transcriptomic data from the U-BIOPRED cohort identified severe asthma groups with features consistent with the presence of IL-13 and EGFR/ERBB activation, with involvement of distinct EGFR ligands. Our data suggest that IL-13 may play a dual role in severe asthma: on the one hand driving pathologic corticosteroid-refractory mixed granulocytic inflammation, but on the other hand underpinning beneficial epithelial repair responses, which may confound responses in clinical trials. Conclusion and ClinicalRelevance: Detailed dissection of those molecular pathways that are downstream of IL-13 and utilize the ERBB receptor and ligand family to drive corticosteroid-refractory inflammation should enhance the development of new treatments that target this sub-phenotype(s) of severe asthma, where there is an unmet need. K E Y W O R D S animal models, asthma, basic mechanisms, corticosteroid-refractory, epithelium, neutrophils | 673 DAVIES Et Al.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Involvement of the epidermal growth factor receptor in IL‐13–mediated corticosteroid‐resistant airway inflammation

Davies

Perotin-Collard

Kelly

et al. 2020

Clin Experimental Allergy

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“…For example, EGFR is a surface protein that binds to the epidermal growth factor and is expressed in many cell types of the lungs, including smooth muscle cells, endothelial cells, broblasts, and epithelial cells [63]. Its immunoreactivity induces the production of mucin in the airway and airway remodeling [64] and triggers airway in ammation by activating intracellular signaling pathways [65]. Signal transducer and activator of transcription-3 (STAT-3) plays an important role in the development and maturation of tissue functions in vertebrates, including in ammation control and immunity [66].…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology-based Analysis of the Molecular Mechanism of Tanreqing in the Treatment of the Coronavirus Disease 2019 (COVID-19)

Yang

Wen

Zheng

et al. 2020

Preprint

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Background: This paper discusses the molecular mechanism of Tanreqing (TRQ) in the treatment of the coronavirus disease 2019 (COVID-19) using the network pharmacology approach. Our study provides new ideas on the laboratory research and clinical treatment of the disease. Method: Information on the chemical constituents of TRQ and the genes targeted by the disease was collected. The common gene targets of the drug and the disease were input into the Search Tool for the Retrieval of Interacting Genes/Proteins（STRING）database to understand the interaction among target proteins. The protein–protein interaction (PPI) network and a network of the chemical constituents of TRQ and their targets were constructed using Cytoscape. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the R program and other relevant software packages. Results: Twenty-eight active chemical constituents and 365 gene targets were identified for TRQ. Out of these genes, 113 were also found to be involved in the pathogenesis of the disease. Enrichment analysis revealed the therapeutic role that TRQ could have played in the treatment of COVID-19, via the regulation of important pathways such as the renin–angiotension system, neuroactive ligand–receptor interaction, phospholipase D (PLD) signaling pathway, calcium signaling pathway, and the hypoxia-inducible factor 1 (HIF-1) signaling pathway. Conclusions: This study attempts to predict the molecular mechanism of TRQ in the treatment of COVID-19, and suggests TRQ intervention through multiple targets and pathways in processes including inflammatory response, immune regulation, and apoptosis during the treatment of the disease. This study indicates the potential rational application of TRQ in the clinical treatment of COVID-19.

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“…EGFR is an epidermal growth factor receptor that is widely distributed in epithelial tissues and plays an important regulatory role in the development of respiratory in ammation [20,21,22]. EGFR inhibitors can effectively inhibit acute in ammation of the rat respiratory tract caused by exogenous zinc ions [23].…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory Mechanism of Rhein in Treating Asthma Based on Network Pharmacology

Feng

Chen

Wang

2020

Preprint

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Background: Network pharmacological methods were used to predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma, and to elucidate its mechanism of action. In addition, we validated the anti-inflammatory effects of rhein in HBE cells. Methods: The corresponding targets of rhein were obtained from the TCMSP 2.3, and molecular docking was also performed. A network of predicted rhein targets was established and analysed with Cytoscape 3.7.1. The anti-inflammatory targets in the TTD database were searched to build a PPI network, which was merged with the ingredient-target network to screen anti-inflammatory targets associated with rhein. A network of anti-inflammatory rhein targets during the in vivo treatment of asthma was constructed to screen the anti-inflammatory targets related to asthma. KEGG enrichment analysis was performed with the Enrichr database and Cytoscape 3.7.1. The expression levels of proteins in the MAPK/NF-κB signalling pathway were assessed by western blot analysis. Results: Altogether, 17 targets were obtained. Epidermal active growth factor receptor (EGFR), E-selecting (E-SELE), macrophage migration inhibitory factor (MIF), and mitogen-activated protein kinase 14 (MAPK14) might be important anti-inflammatory targets of rhein during asthma treatment. We selected the MAPK signalling pathway to determine the anti-inflammatory effects of rhein. Conclusion: The anti-inflammatory mechanism of the treatment of asthma with rhein may be related to MAPK14, EGFR, E-SELE and MIF as well as their signalling pathways. To prevent the exacerbation of asthma, instead of targeting a single pathway or a single target, all these targets and their signalling pathways should be controlled holistically. Rhein may reduce inflammation by inhibiting the MAPK/NF-κB pathway.

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Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model

Cited by 62 publications

References 56 publications

Involvement of the epidermal growth factor receptor in IL‐13–mediated corticosteroid‐resistant airway inflammation

Involvement of the epidermal growth factor receptor in IL‐13–mediated corticosteroid‐resistant airway inflammation

A Network Pharmacology-based Analysis of the Molecular Mechanism of Tanreqing in the Treatment of the Coronavirus Disease 2019 (COVID-19)

Anti-inflammatory Mechanism of Rhein in Treating Asthma Based on Network Pharmacology

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