Impaired airway epithelial cell wound‐healing capacity is associated with airway remodelling following RSV infection in severe preschool wheeze. Issue 12 (15th July 2020)

• Record Type: Journal Article
• Authors: Andersson, Cecilia K.; Iwasaki, Jua; Cook, James; Robinson, Polly; Nagakumar, Prasad; Mogren, Sofia; Fleming, Louise; Bush, Andrew; Saglani, Sejal; Lloyd, Clare M.
• Is Part Of: Allergy. Volume 75:Issue 12(2020)
• Page Start: 3195
• Page End: 3207
• Publication Date: 2020-07-15
• Subjects: epithelium -- paediatric asthma -- RSV -- severe therapy‐resistant asthma -- wheeze; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.14466
• Languages: English
• ISSNs: 0105-4538

Abstract

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 non‐asthmatic 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. Abstract : In response to RSV, PBECs from children with STRA and PSW demonstrate increased TLR3 gene expression and enhanced secretion of pro‐inflammatory cytokines compared to controls. IL‐33 expression correlates with collagen deposition in children with STRA and PSW. Despite the increased antiviral responses, airway epithelial proliferative responses following barrier damage are impaired in children with PSW. Abbreviations: EGFR, epithelial growth factor receptor; IFN‐γ, interferon‐γ; IP‐10, IFN‐γ‐inducible protein 10; PBECs, primary bronchial epithelial cells; PSW, pre‐school wheeze; RSV, respiratory syncytial virus; STRA, severe therapy resistant asthma; TLR3, toll‐like receptor