We observed an unexpectedly high incidence of postoperative airway dehiscence in lung-transplant recipients treated with sirolimus, in combination with tacrolimus, prednisone, and an HMG-CoA inhibitor. Further studies will be needed to determine the safety and efficacy of using sirolimus after complete airway healing has occurred.
Acute lung injury leads to type I alveolar epithelial cell (AEC) death, denudation of the alveolar basement membrane, and formation of an alveolar provisional matrix from fibronectin, fibrinogen, and type I collagen. The provisional matrix provides a scaffold for alveolar repair. To restore normal lung architecture, surviving type II AECs must reepithelialize denuded alveoli. We examined whether AECs migrate on provisional matrix proteins and whether integrins mediate this migration using a Boyden chemotaxis chamber. Cultured AECs migrated on fibronectin-coated filters by haptotaxis (defined as movement on a solid-phase substrate) more than one type I collagen-coated filters, and they did not migrate on fibrinogen-coated filters. Soluble fibronectin augmented migration on type I collagen-coated filters, but not on fibronectin-coated filters. Anti-alpha v beta 3-integrin monoclonal antibody (MAb) inhibited migration on substrate-bound fibronectin by 62-77%, whereas anti-beta 1-integrin MAb inhibited migration by 48%. Anti-alpha 2-integrin MAb almost completely inhibited migration on substrate-bound type I collagen, but not on fibronectin. The novel findings in this study are as follows: 1) AECs migrate by haptotaxis more effectively on substrate-bound fibronectin than on type I collagen; 2) alpha v beta 3- and beta 1-integrins partially mediate AEC haptotaxis on fibronectin; and 3) the alpha 2 beta 1-integrin mediates AEC migration on type I collagen. These results support the importance of type II cell migration on provisional matrix proteins during repair of lung injury.
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.
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