Epithelial to Mesenchymal Transition (EMT) and Airway Remodelling after Human Lung Transplantation.

Lee A Borthwick ¹, Sean M Parker ¹, Kathrine A Brougham ¹, Gail E Johnson ¹, Marta R Gorowiec ¹, Chris Ward ¹, James Lordan ¹, Paul Corris ¹, John A Kirby ¹ and Andrew J Fisher ^1*

¹ Newcastle University, United Kingdom

^* To whom correspondence should be addressed. E-mail: a.j.fisher{at}newcastle.ac.uk.

Accepted 21 January 2009

Abstract

Background: Aberrant epithelial repair is a key event in the airway remodelling which characterises obliterative bronchiolitis (OB) in the transplanted lung. The potential for airway epithelium from lung transplant recipients to undergo epithelial to mesenchymal cell transition (EMT) was assessed in culture and in vivo in lung allograft tissue.

Methods: Changes in epithelial and mesenchymal marker expression was assessed after stimulation with TGF-1 alone or in combination with TNF and compared to untreated controls. Cells ability to deposit extra-cellular matrix, secrete matrix metalloproteinases and invade collagen were investigated. Immunolocalisation of epithelial and mesenchymal markers were compared in airway tissue from stable recipients and those with OB.

Results: Untreated cells maintain epithelial morphology and phenotype. TGF-1 reduced expression of epithelial markers, increased expression of vimentin and fibronectin, promoted collagen I and fibronectin deposition and increased MMP-9 production. Co-treatment with TNF dramatically accentuated phenotypic and some functional features of EMT. Airway epithelial biopsies from recipients with OB demonstrated significantly increased staining for mesenchymal markers and significantly reduced E-cadherin staining compared to stable recipients.

Conclusions: These observations demonstrate the ability of human airway epithelium to undergo EMT and suggest this phenomenon may be a potential link between inflammatory injury and TGF-1 driven airway remodelling in the development of OB.