CYCLOSPORINE REDUCES DEVELOPMENT OF OBLITERATIVE BRONCHIOLITIS IN A MURINE HETEROTOPIC AIRWAY MODEL

Obliterative bronchiolitis (OB), an important threat to the long-term survival of lung transplant recipients, is characterized histologicall y by fibroproliferation within small airways. The pathogenesis of OB i s thought to involve chronic allograft rejection, and therapy frequent ly includes augmentation of immunosuppression. We have developed a mod el that reproduces the pathologic lesion of OB and allows study of int erventions designed to limit airway fibrosis. In this model, heterotop ic transplantation of murine airways into immune-mismatched recipients results in epithelial abnormalities and fibroproliferation in the air way lumen, changes not seen in heterotopic isografts. Cyclosporine (Cs A) inhibits activation and proliferation of T lymphocytes and is commo nly administered after lung transplantation. We hypothesized that use of CsA in our model system would reduce fibroproliferation in tracheal allografts. To test this hypothesis, murine tracheas were transplante d heterotopically into allomatched and allomismatched recipients, and then treated with varying doses (5, 10, 15, or 25 mg/kg i.p. q.d.) of CsA. Controls included allografts and isografts not treated with CsA. After 30 days, tracheas were harvested and examined histologically. Cs A markedly reduced the development of fibroproliferation in allografts (19% in treated allografts versus 90% in untreated allografts, P<0.00 01), but did not reduce inflammation or airway epithelial cell injury. High-dose (25 mg/kg/day) CsA was more effective than lower doses in r educing fibroproliferation (0% in high dose versus 29% in low dose, P= 0.04). These findings demonstrate that CsA significantly reduces devel opment of the pathologic lesion of OB, and supports the role of alloim munity in the pathogenesis of this disease.