Impaired airway epithelial cell wound‐healing capacity is associated with airway remodelling following RSV infection in severe preschool wheeze

Abstract

Background: Respiratory syncytial virus (RSV) causes exacerbations of asthma and preschool wheeze (PSW). However, the anti-viral and repair responses of the bronchial epithelium in children with severe therapy-resistant asthma (STRA) and PSW are poorly understood. Methods: Children with STRA (age 12 [6-16] years), PSW (age 2 [1-5] years) and nonasthmatic controls (age 7 [2-14] years) underwent bronchoscopy with endobronchial brushings and biopsies. Anti-viral, wound injury responses were quantified in biopsies and primary bronchial epithelial cells (PBECs) in response to RSV, poly(I:C), house dust mite (HDM) or IL-33 using RT-qPCR, Luminex and live cell imaging. Collagen deposition and tissue expression of epithelial growth factor receptor (EGFR), IL-33 and receptor ST2 were investigated in bronchial biopsies. Results: PBECs from STRA and PSW had increased TLR3 gene expression and increased secretion of anti-viral and pro-inflammatory cytokines (IFN-γ, IL-6 and IL-13) in response to RSV compared to controls. Exposure of PBECs to concomitant TLR3 agonist poly(I:C) and HDM resulted in a significant reduction in epithelial cell proliferation in PSW compared to controls. Wound-healing was also impaired in PSW compared to controls at baseline and following IL-33 stimulation. In addition, tissue EGFR expression was significantly reduced in PSW and correlated with collagen deposition in endobronchial biopsies. Conclusions: Despite increased anti-viral responses, preschool children with severe wheeze had impaired airway epithelial proliferative responses following damage. This might be connected to the low expression of EGFR in PSW which may affect epithelial function and contribute to asthma pathogenesis.

Mast cell tryptase enhances wound healing by promoting migration in human bronchial epithelial cells

“…Other factors that cause migratory effects in epithelial cells are growth factors TGF-β, EGF and AREG which have been shown to increase in asthma [45,46]. Our study has shown that tryptase promotes expression of growth factors FGF2 and PDGF-AA in bronchial epithelial cells (Figure 4(b-c)).…”

ERS International Congress 2021: highlights from the Paediatric Assembly

“…F ayon et al [ 19 ] received the award for the best abstract of the Paediatric Assembly. This study aimed to identify clusters of preschool children with recurrent wheeze who are at higher risk of developing asthma based on bronchial remodelling features [ 20 ]. They performed fibre optic bronchoscopy in 56 preschool children with persistent wheeze and identified histological parameters that were stronger predictors of asthma development.…”

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

“…In children with therapy resistant asthma, bronchoscopic investigation and brushing suggested that wound repair of the epithelium was delayed compared to pre-school children with wheezing [43]. Epithelial cells from these patients showed reduced ability to overcome respiratory syncytial virus infection despite their increased secretion of anti-viral cytokines.…”

“…Thus, epithelial cells communicate with immune cells and sub-epithelial tissue forming cells. Interestingly, several studies suggested that the airway epithelial cells have some sort of "memory" of previous infections or damages, which is linked to the immune response [43,44,84]. In another study, new variants of genes encoding for TNF receptors and TGF-β receptors were identified as risk factors for airway wall remodeling in asthma [85].…”