The phenotype of airway epithelial cells suggests epithelial to mesenchymal cell transition in clinically stable lung transplant recipients

Christopher Ward ¹, Ian A Forrest ¹, Desmond M Murphy ¹, Gail E Johnston ¹, Helen Robertson ¹, Tim E Cawston ¹, Andrew J Fisher ¹, John H Dark ¹, James L Lordan ¹, John A Kirby ¹ and Paul A Corris ^1*

¹ University of Newcastle upon Tyne, United Kingdom

^* To whom correspondence should be addressed. E-mail: paul.corris{at}ncl.ac.uk.

Accepted 14 June 2005

Abstract

Background:Obliterative bronchiolitis in chronic rejection of lung allografts is characterised by airway epithelial damage and fibrosis. The process whereby normal epithelium is lost and replaced by fibroblastic scar tissue is poorly understood but recent findings suggest that epithelial cells can become fibroblasts through epithelial mesenchymal transition (EMT).

Hypothesis:Epithelial mesenchymal transition occurs in lung allografts and plays a potential role in airway remodelling.

Methods:Sixteen stable lung transplant recipients underwent bronchoscopy with bronchoalveolar lavage (BAL), endobronchial biopsies and bronchial brushings. Biopsy sections were stained for the fibroblast marker S100A4. Brushings were cultured on collagen, stained with anti-S100A4 and examined for further EMT markers including Matrix metalloproteinase (MMP) zymographic activity, and epithelial invasion through collagen coated filters.

Results:A median 15% (0-48 %) of the biopsy epithelium stained for S100A4 in stable lung transplant recipients and MMP-7 co-localisation was observed. In un- stimulated epithelial cultures from lung allografts S100A4 staining was identified, with MMP-2 and MMP-9 production and zymographic activity. MMP total protein and activity was increased following Transforming Growth Factor-1 stimulation. Unstimulated transplant epithelial cells were invasive and penetration of collagen coated filters increased following TGF- 1 stimulation.

Discussion:We provide evidence of EMT markers in the lung allografts of patients without loss of lung function. The EMT process may represent a final common pathway following injury in more common diseases characterised by airway remodelling.

Keywords: epithelium, fibroblasts, lung transplantation

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