期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 10, 期 3, 页码 498-509出版社
WILEY
DOI: 10.1111/j.1600-6143.2009.02953.x
关键词
Bronchiolitis obliterans syndrome; epithelial mesenchymal transition; interleukin-1; macrophage; obilterative bronchiolitis; transforming growth factor-ss 1; tumor necrosis factor alpha
资金
- Medical Research Council UK [G0700861]
- GlaxoSmithKline
- Medical Research Council [G0500705, G0700861, G0800419] Funding Source: researchfish
- MRC [G0700861, G0800419, G0500705] Funding Source: UKRI
Epithelial to mesenchymal transition (EMT) has been implicated in the pathogenesis of obliterative bronchiolitis (OB) after lung transplant. Although TNF-alpha accentuates TGF-beta 1 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-beta 1 +/- IL-1 beta, 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-beta 1 + TNF-alpha or IL-1 beta significantly accentuates phenotypic and some functional features of EMT compared to TGF-beta 1 alone. Co-treatment with TGF-beta 1 + TNF-alpha or IL-1 beta accelerates epithelial wound closure however the quality of repair is highly dysregulated. Co-treatment with TGF-beta 1 + IL-8 has no significant effect on EMT or the speed or quality of wound healing. Activated macrophages dramatically accentuate TGF-beta 1-driven EMT and cause dysregulated wound repair. Crosstalk between macrophage-derived acute inflammation in the airway and elevated TGF-beta 1 may favor dysregulated airway epithelial repair and fibrosis in the lung allograft via EMT.
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