Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.
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.
Kuo
Elbert
E
Department of Surgery, Washington University, St. Louis, Missouri 63110, USA.
Bharat
Ankit
A
Shih
Jennifer
J
Street
Tyler
T
Norris
Jenyi
J
Liu
Wei
W
Parks
William
W
Walter
Michael
M
Patterson
G Alexander
GA
Mohanakumar
T
T
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
D020783:Matrix Metalloproteinase 7