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

被引：57
作者：
Borthwick, L. A. [1 ]
McIlroy, E. I. [1 ]
Gorowiec, M. R. [1 ]
Brodlie, M. [1 ]
Johnson, G. E. [1 ]
Ward, C. [1 ]
Lordan, J. L. [1 ]
Corris, P. A. [1 ]
Kirby, J. A. [1 ]
Fisher, A. J. [1 ]
机构：
[1] Newcastle Univ, Inst Cellular Med, Appl Immunobiol & Transplantat Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
来源：
AMERICAN JOURNAL OF TRANSPLANTATION | 2010年 / 10卷 / 03期
基金：
英国医学研究理事会;
关键词：
Bronchiolitis obliterans syndrome; epithelial mesenchymal transition; interleukin-1; macrophage; obilterative bronchiolitis; transforming growth factor-ss 1; tumor necrosis factor alpha; BRONCHIOLITIS-OBLITERANS-SYNDROME; GROWTH-FACTOR-BETA; TGF-BETA; PULMONARY-FIBROSIS; SIGNAL-TRANSDUCTION; CELL TRANSITION; KAPPA-B; EXPRESSION; AZITHROMYCIN; DISEASE;
D O I：
10.1111/j.1600-6143.2009.02953.x
中图分类号：
R61 [外科手术学];
学科分类号：
摘要：
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.
引用
收藏
页码：498 / 509
页数：12
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