Tim Brazelton

BACKGROUND: The etiology and pathogenesis of obliterative bronchiolitis after lung transplantation remain to be fully elucidated. Using a rat model of heterotopically transplanted trachea grafts, we have examined the role airway epithelium plays in obliterative airway disease (OAD). METHODS: Rat trachea isografts were denuded of epithelium by protease digestion. Grafts were inoculated either with or without native airway epithelial cells and transplanted into the omentum of recipient animals. RESULTS: Airway epithelium removal resulted in OAD in denuded isogeneic trachea grafts. Reseeding of the denuded grafts with epithelial cells significantly reduced airway obliteration from 78% to 22% luminal occlusion. CONCLUSIONS: Non-immune-mediated injury will cause OAD, and epithelial cell replacement in denuded isografts can significantly reduce the fibrotic progression of the disease.

BACKGROUND: Because epithelial cells are targets of alloimmune injury leading ultimately to airway obliteration, we tested whether epithelial re-growth could prevent obliterative airway disease (OAD) in orthotopic tracheal allografts. METHODS: Brown Norway tracheal segments were orthotopically transplanted into nonimmunosuppressed Lewis rats. Allografts were removed on days 2-10 (n=13), 30 (n=4), and 60 (n=5) for histology, computerized morphometry (obliteration), and immunohistochemical detection of mononuclear cells, smooth muscle alpha-actin, and tissue phenotype. Normal tracheas, host tracheas, and heterotopically transplanted allografts served as controls. RESULTS: Orthotopic allografts removed on days 2-10 exhibited epithelial damage and re-growth and mononuclear cell infiltration. On days 30 and 60, partially ciliated cuboidal or attenuated epithelium completely covered the lumen. Although mononuclear cells declined, numerous T cells with a high CD4/CD8 ratio were found in the epithelium till day 60. Orthotopic allograft epithelium expressed donor phenotype on day 7, but recipient phenotype on days 30 and 60. Despite subepithelial alpha-actin positive myofibroblast proliferation, obliteration did not progress from day 7 to 30 and 60 (35, 30, and 33%, respectively). Although more than in normal or host tracheas, the obliteration in orthotopic allografts on days 30 and 60 was significantly less (P<0.001) than in heterotopic allografts. CONCLUSIONS: We describe, for the first time, longterm patency of fully histoincompatible orthotopic tracheal allografts in nonimmunosuppressed rats. Despite acute alloimmune injury and induction of myofibroblast proliferation, epithelial re-growth from the host limited the progression of OAD, thus emphasizing the role of epithelium in the control of airway obliteration.