title: Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.
abstract: BACKGROUND
  Murine tracheal transplantation is a model used to study bronchiolitis obliterans syndrome, a major cause of morbidity and mortality after lung transplantation. Unlike murine heterotopic tracheal transplants, orthotopic transplantation does not cause luminal obliteration despite major histocompatibility antigen mismatch. Repopulation of the tracheal allografts with recipient-derived epithelium confers protection against luminal obliteration. The purpose of this study was to determine whether (1) orthotopic tracheal transplantation showed signs of allograft rejection, and (2) airway epithelial cell injury promoted orthotopic tracheal allograft rejection.
  
  
  METHODS
  Forty isogeneic (C57BL/6 to C57BL/6) and 40 allogeneic (BALB/c to C57BL/6) orthotopic tracheal transplants were performed. Damage to airway epithelial cells was induced by Sendai viral (SdV) infection and tracheal transplantation into non-reepithelializing matrix metalloproteinase-7 knockout (MMP7-KO) recipient mice. Percent fibrosis and lamina propria to cartilage ratio were calculated with computer assistance on harvested allografts.
  
  
  RESULTS
  Allografts showed significantly more intramural fibrosis compared with isografts at 30, 60, and 180 days after transplant without luminal occlusion. Tracheal allografts infected with SdV showed an increase in fibrosis and lamina propria to cartilage ratio compared with noninfected controls. Allografts retrieved from MMP7-KO recipients also showed a significant increase in fibrosis and lamina propria to cartilage ratio.
  
  
  CONCLUSIONS
  Although orthotopic tracheal transplantation does not cause luminal obliteration, it results in increased fibrosis in allografts. Damage to the respiratory epithelium by viral infection or defective reepithelialization after transplant as seen in MMP7-KO recipient mice leads to changes consistent with chronic allograft rejection, suggesting a role for epithelial injury in bronchiolitis obliterans syndrome development.
authors.affiliation: Department of Surgery, Washington University, St. Louis, Missouri 63110, USA.
authors.forename: Elbert
authors.initials: E
authors.lastname: Kuo
authors.forename: Ankit
authors.initials: A
authors.lastname: Bharat
authors.forename: Jennifer
authors.initials: J
authors.lastname: Shih
authors.forename: Tyler
authors.initials: T
authors.lastname: Street
authors.forename: Jenyi
authors.initials: J
authors.lastname: Norris
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: William
authors.initials: W
authors.lastname: Parks
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: G Alexander
authors.initials: GA
authors.lastname: Patterson
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000473:pathology*; D004195:Disease Models, Animal; D005355:Fibrosis; D006084:Graft Rejection / Q000473:pathology*; D020783:Matrix Metalloproteinase 7; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016377:Organ Transplantation / Q000473:pathology; D020545:Respiratory Mucosa / Q000473:pathology*; D012141:Respiratory Tract Infections / Q000150:complications / Q000821:virology*; D010253:Respirovirus Infections / Q000150:complications; D029082:Sendai virus; D014132:Trachea / Q000473:pathology* / Q000637:transplantation; D014184:Transplantation, Homologous
chemical_list: D020783:Matrix Metalloproteinase 7