title: Epithelial to mesenchymal transition in murine tracheal allotransplantation: an immunohistochemical observation.
abstract: BACKGROUND
  Aberrant epithelial repair is a crucial event in the airway remodeling that characterizes obliterative bronchiolitis (OB) in transplanted lungs. Recent data from experiments using epithelial cell lines and human airway tissues from lung transplant recipients suggest that epithelial to mesenchymal transition (EMT) plays an important role in OB. The aim of this study was to clarify whether EMT is involved in airway remodeling in an animal model.
  
  
  METHODS
  We performed orthotopic tracheal transplantation from BALB/c to C57BL/6 mice with from BALC/c to BALB/c mouse grafts as controls. Five allogeneic and 3 syngeneic recipients were humanely killed at predetermined postoperative days 2-12 as well as 14 and 21. Histology was evaluated using hematoxylin-eosin (H&E) staining. We studied the expression of specific markers, including E-cadherin, an epithelial marker; α-smooth muscle actin (SMA), and S100A4, mesenchymal markers, and zinc finger E-box-binding homeobox 1 (ZEB1), an EMT-related transcription factor.
  
  
  RESULTS
  Histologic assessment of serial H&E stains of allogeneic grafts showed remarkable pseudostratified respiratory epithelium with subepithelial inflammatory cell infiltration, as well as denuded and flattened epithelium and subepithelial fibrosis. The dynamic epithelial changes occurred earlier than the subepithelial fibrosis. Immunohistochemical evaluation indicated the emergence of α-SMA- positive epithelial cells that were most prominent on day 7. The expression of E-cadherin was attenuated in α-SMA-positive epithelial cells. S100A4 was also expressed in epithelial cells. A few days before the intraepithelial expression of α-SMA, ZEB1 emerged in the nuclei of epithelial cells.
  
  
  CONCLUSIONS
  We observed expression of an EMT-related transcription factor and mesenchymal markers along with the attenuation of epithelial marker expression in epithelial cells, several days before prominent subepithelial fibrosis formation, results that suggest epithelial cells to play an important fibrosis role in airway remodeling during epithelial to mesenchymal transition.
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, University of Tokyo, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Konoeda
authors.forename: D
authors.initials: D
authors.lastname: Koinuma
authors.forename: Y
authors.initials: Y
authors.lastname: Morishita
authors.forename: A
authors.initials: A
authors.lastname: Sano
authors.forename: K
authors.initials: K
authors.lastname: Nagayama
authors.forename: N
authors.initials: N
authors.lastname: Motomura
authors.forename: K
authors.initials: K
authors.lastname: Kakimi
authors.forename: K
authors.initials: K
authors.lastname: Miyazono
authors.forename: J
authors.initials: J
authors.lastname: Nakajima
authors.forename: M R
authors.initials: MR
authors.lastname: Nicolls
authors.forename: T
authors.initials: T
authors.lastname: Murakawa
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D014132:Trachea / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D014184:Transplantation, Homologous