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Ann Thorac Surg 2006;82:1226-1233
© 2006 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Role of Airway Epithelial Injury in Murine Orthotopic Tracheal Allograft Rejection

^a Department of Surgery, Washington University, St. Louis, Missouri
^b Department of Pathology and Immunology, Washington University, St. Louis, Missouri
^c Department of Pulmonary and Critical Care, Washington University, St. Louis, Missouri
^d Department of Medicine, University of Washington School of Medicine, Seattle, Washington

Accepted for publication March 31, 2006.

^_* Address correspondence to Dr Mohanakumar, Washington University School of Medicine, Department of Surgery, Box 8109, 660 S Euclid Ave, St. Louis, MO 63110 (Email: kumart{at}wustl.edu).

Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.

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.

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