Combined SDZ Rad and Cyclosporine a Prevent Fibrosis, but Not Lymphocyte Infiltration, in Experimental Obliterative AIrways Disease

This is the authors' abstract. We don't add key points for this paper.

179 Obliterative bronchiolitis after lung transplantation is believed to result from an alloimmune response followed by fibroproliferation. Rapamycin (RPM) and cyclosporine A (CSA) exert immunosuppressive effects by inhibiting distinct steps in the process of alloimmune-induced T-cell activation and proliferation, and RPM also has an antiproliferative effect on mesenchymal cells. Therefore, we hypothesized that a RPM-class drug+CSA would be more potent than either agent alone in inhibiting inflammation and fibrosis in the heterotopic rat tracheal transplant model of obliterative airways disease (OAD). To investigate this hypothesis, Lewis tracheal allografts were transplanted subcutaneously into Brown Norway recipients. Two doses of SDZ RAD [RAD; 40-O-(2-hydroxyethyl)-rapamycin] and CSA microemulsion, alone and in combination, were administered daily by gavage. Grafts were harvested 34 days after transplantation and examined histopathologically for inflammatory cell infiltrate and abnormal epithelium, graded 0 (normal) to 4; and for fibrosis, expressed as proportion lumenal occlusion: (Table)TableRAD grafts had less fibrosis than CSA grafts. RAD+CSA grafts showed no fibrosis despite marked mural and intraepithelial lymphocytic infiltration. In addition, RAD+CSA grafts had ciliated respiratory epithelium, while other grafts had flattened or absent epithelium. We conclude that RAD limits fibrosis, and RAD+CSA permits the growth of ciliated respiratory epithelium in this model of OAD. The increase in lymphocytic infiltration and the apparent dissociation of lymphocytic infiltration and fibrosis in RAD+CSA grafts are unique observations which deserve further study.