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

Lookup NU author(s): Dr Lee Borthwick, Marta Gorowiec, Dr Malcolm Brodlie, Dr Christopher Ward, Dr James Lordan, Professor Paul Corris, Professor John Kirby, Professor Andrew Fisher

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Abstract

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.


Publication metadata

Author(s): Borthwick LA, McIlroy EI, Gorowiec MR, Brodlie M, Johnson GE, Ward C, Lordan JL, Corris PA, Kirby JA, Fisher AJ

Publication type: Article

Publication status: Published

Journal: American Journal of Transplantation

Year: 2010

Volume: 10

Issue: 3

Pages: 498-509

Print publication date: 05/01/2010

ISSN (print): 1600-6135

ISSN (electronic): 1600-6143

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1111/j.1600-6143.2009.02953.x

DOI: 10.1111/j.1600-6143.2009.02953.x


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