EGF-Induced Bronchial Epithelial Cells Drive Neutrophil Chemotactic and Anti-Apoptotic Activity in Asthma
Author(s)
Type
Journal Article
Abstract
Chronic damage and repair of the bronchial epithelium are features of asthma. We have previously reported that ex vivo stimulation of normal bronchial epithelial cells with epidermal growth factor (EGF), a key factor of epithelial repair, enhances the mechanisms of neutrophil accumulation, thereby promoting neutrophil defences during acute injury but potentially enhancing inflammation in chronic airway diseases. We have now sought to (i) determine whether this EGF-dependent pro-neutrophil activity is increased in asthma, where EGF and its epithelial receptor are over-expressed, and (ii) elucidate some of the mechanisms underlying this asthmatic epithelial-neutrophil interaction. Primary bronchial epithelial cells (PBEC) from healthy subjects, mild asthmatics and moderate-to-severe asthmatics (Mod/Sev) were stimulated with EGF, a model that mimics a repairing epithelium. Conditioned culture media (EGF-CM) were assessed for neutrophil chemotactic and anti-apoptotic activities and inflammatory mediator production. EGF induced the epithelium to produce soluble mediators with neutrophil chemotactic (p<0.001) and pro-survival (p = 0.021) activities which were related to the clinical severity of asthma (trend p = 0.010 and p = 0.009, respectively). This was associated with enhanced IL-6, IL-8, GM-CSF and TNF-α release, and cytokine-neutralising experiments using EGF-CM from Mod/Sev asthmatics demonstrated a role for GM-CSF in neutrophil survival (p<0.001). Pre-treatment of neutrophils with specific inhibitors of the myeloid-restricted class I phosphatidylinositol-3-OH kinase (PI(3)K) isoforms showed that the EGF-CM from Mod/Sev asthmatics depended on the γ (p<0.021) but not δ isoforms, while neutrophil survival required multiple class I PI(3)Ks. The EGF-induced chemotactic, but not pro-survival activity, involved RhoA signaling in neutrophils (p = 0.012). EGF whose activity is upregulated in asthma induces ex vivo the epithelium from asthmatic patients to produce pro-neutrophil activities; these are related to asthma severity and, in moderate-to-severe asthmatics, involves class IB PI(3)Kγ signaling, providing a potential therapeutic target for neutrophilic forms of asthma.
Date Issued
2013-09-11
Online Publication Date
2013-09-11
2016-07-12T08:54:49Z
Date Acceptance
2013-07-10
ISSN
1932-6203
Publisher
Public Library of Science
Journal / Book Title
PLOS One
Volume
8
Issue
9
Copyright Statement
© 2013 Uddin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Database
pubmed
Subjects
Adult
Apoptosis
Asthma
Bronchi
Case-Control Studies
Cell Proliferation
Cells, Cultured
Chemokines
Chemotaxis, Leukocyte
Culture Media, Conditioned
Epidermal Growth Factor
Epithelial Cells
Female
Humans
Male
Middle Aged
Neutrophils
Phosphatidylinositol 3-Kinases
Respiratory Mucosa
rhoA GTP-Binding Protein
General Science & Technology
MD Multidisciplinary
Publication Status
Published
Country
United States
Article Number
e72502