Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation.
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
Change in epithelial and mesenchymal marker expression was assessed after stimulation with transforming growth factor beta(1) (TGF-beta(1)) alone or in combination with tumour necrosis factor alpha (TNFalpha) and compared with untreated controls. The ability of cells to deposit extracellular matrix, secrete matrix metalloproteinases (MMPs) and invade collagen was investigated. Immunolocalisation of epithelial and mesenchymal markers was compared in airway tissue from stable recipients and those with OB.


RESULTS
Untreated cells maintained epithelial morphology and phenotype. TGF-beta(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 TNFalpha 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 with 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-beta(1)-driven airway remodelling in the development of OB.
Borthwick
L A
LA
Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.
Parker
S M
SM
Brougham
K A
KA
Johnson
G E
GE
Gorowiec
M R
MR
Ward
C
C
Lordan
J L
JL
Corris
P A
PA
Kirby
J A
JA
Fisher
A J
AJ
D056151:Airway Remodeling / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D055745:Bronchioles / Q000473:pathology*; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D054338:Cell Transdifferentiation / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D016040:Lung Transplantation / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D015415:Biomarkers; D015820:Cadherins; D005353:Fibronectins; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D020780:Matrix Metalloproteinase 9