Cyclosporine reduces development of obliterative bronchiolitis in a murine heterotopic airway model.

TitleCyclosporine reduces development of obliterative bronchiolitis in a murine heterotopic airway model.
Publication TypeJournal Article
Year of Publication1997
AuthorsKing MB, Jessurun J, Savik SK, Murray JJ, Hertz MI
Date Published1997 Feb 27
KeywordsAnimals, Bronchiolitis Obliterans, Cyclosporine, Graft Rejection, Immunosuppressive Agents, Lung Transplantation, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Trachea

Obliterative bronchiolitis (OB), an important threat to the long-term survival of lung transplant recipients, is characterized histologically by fibroproliferation within small airways. The pathogenesis of OB is thought to involve chronic allograft rejection, and therapy frequently includes augmentation of immunosuppression. We have developed a model that reproduces the pathologic lesion of OB and allows study of interventions designed to limit airway fibrosis. In this model, heterotopic transplantation of murine airways into immune-mismatched recipients results in epithelial abnormalities and fibroproliferation in the airway lumen, changes not seen in heterotopic isografts. Cyclosporine (CsA) inhibits activation and proliferation of T lymphocytes and is commonly 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 transplanted heterotopically into allo matched 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. CsA markedly reduced the development of fibroproliferation in allografts (19% in treated allografts versus 90% in untreated allografts, P<0.0001), but did not reduce inflammation or airway epithelial cell injury. High-dose (25 mg/kg/day) CsA was more effective than lower doses in reducing fibroproliferation (0% in high dose versus 29% in low dose, P=0.04). These findings demonstrate that CsA significantly reduces development of the pathologic lesion of OB, and supports the role of alloimmunity in the pathogenesis of this disease.

Alternate JournalTransplantation
PubMed ID9047145
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Jose Jessurun, M.D.

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