title: Inflammation and epithelial to mesenchymal transition in lung transplant recipients: role in dysregulated epithelial wound repair.
abstract: Epithelial to mesenchymal transition (EMT) has been implicated in the pathogenesis of obliterative bronchiolitis (OB) after lung transplant. Although TNF-alpha accentuates TGF-beta1 driven EMT in primary human bronchial epithelial cells (PBECs), we hypothesized that other acute pro-inflammatory cytokines elevated in the airways of patients with OB may also accentuate EMT and contribute to dysregulated epithelial wound repair. PBECs from lung transplant recipients were stimulated with TGF-beta1+/-IL-1beta, IL-8, TNF-alpha or activated macrophages in co-culture and EMT assessed. The quality and rate of wound closure in a standardized model of lung epithelial injury was assessed in response to above stimuli. Co-treatment with TGF-beta1+TNF-alpha or IL-1beta significantly accentuates phenotypic and some functional features of EMT compared to TGF-beta1 alone. Co-treatment with TGF-beta1+TNF-alpha or IL-1beta accelerates epithelial wound closure however the quality of repair is highly dysregulated. Co-treatment with TGF-beta1+IL-8 has no significant effect on EMT or the speed or quality of wound healing. Activated macrophages dramatically accentuate TGF-beta1-driven EMT and cause dysregulated wound repair. Crosstalk between macrophage-derived acute inflammation in the airway and elevated TGF-beta1 may favor dysregulated airway epithelial repair and fibrosis in the lung allograft via EMT.
authors.affiliation: Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Borthwick
authors.forename: E I
authors.initials: EI
authors.lastname: McIlroy
authors.forename: M R
authors.initials: MR
authors.lastname: Gorowiec
authors.forename: M
authors.initials: M
authors.lastname: Brodlie
authors.forename: G E
authors.initials: GE
authors.lastname: Johnson
authors.forename: C
authors.initials: C
authors.lastname: Ward
authors.forename: J L
authors.initials: JL
authors.lastname: Lordan
authors.forename: P A
authors.initials: PA
authors.lastname: Corris
authors.forename: J A
authors.initials: JA
authors.lastname: Kirby
authors.forename: A J
authors.initials: AJ
authors.lastname: Fisher
mesh_terms: D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004848:Epithelium / Q000473:pathology*; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016040:Lung Transplantation / Q000379:methods*; D008264:Macrophages / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology*; D008954:Models, Biological; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing
chemical_list: D053583:Interleukin-1beta; D016209:Interleukin-8; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha