Inflammation and Epithelial to Mesenchymal Transition in Lung Transplant Recipients: Role in Dysregulated Epithelial Wound Repair

摘要

Epithelial to mesenchymal transition (EMT) has been implicated in the pathogenesis of obliterative bronchiolitis (OB) after lung transplant. Although TNF- accentuates TGF-β1 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-β1 ± IL-1β, IL-8, TNF- 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-β1 + TNF- or IL-1β significantly accentuates phenotypic and some functional features of EMT compared to TGF-β1 alone. Co-treatment with TGF-β1 + TNF- or IL-1β accelerates epithelial wound closure however the quality of repair is highly dysregulated. Co-treatment with TGF-β1 + IL-8 has no significant effect on EMT or the speed or quality of wound healing. Activated macrophages dramatically accentuate TGF-β1-driven EMT and cause dysregulated wound repair. Crosstalk between macrophage-derived acute inflammation in the airway and elevated TGF-β1 may favor dysregulated airway epithelial repair and fibrosis in the lung allograft via EMT.