CYCLOSPORINE A MEDIATES FIBROPROLIFERATION THROUGH EPITHELIAL CELLS

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Abstract
Obliterative bronchiolitis (OB) is the major cause of morbidity and mortality after lung transplantation. The potential role of immunosuppressive drugs in the development of OB is uncertain, but there are limited data indicating that cyclosporine A (CsA) may have a direct fibrogenic effect on various human cell types. Epithelium-fibroblast interactions have been suggested to play a crucial role in the course of fibroproliferation, which is a major feature of OB. We studied the effect of CsA and FK506 on primary human lung fibroblast proliferation in a human epithelial-fibroblast interactive model. Clinically relevant concentrations of CsA (0.1–1 μg/mL) and FK506 (0.001–0.01 μg/mL) did not affect fibroblast proliferation in monocultures. Conditioned medium (CM) from untreated epithelial cells (Calu-3) stimulated fibroblast proliferation. CM from FK506-treated (0.001–0.1 μg/mL) epithelial cells had no significant additive effect on fibroblast proliferation compared with CM of untreated epithelial cells. In contrast, CM obtained from epithelial cells treated with 0.1 μg/mL CsA significantly enhanced fibroblast proliferation compared with CM of untreated epithelial cells. This proliferative effect of 0.1 μg/mL CsA was mediated by epithelial-derived factors greater than 100 kDa. These data demonstrate that a clinically relevant concentration of CsA stimulates fibroblast proliferation through mediators produced by airway epithelial cells, raising the possibility that CsA may contribute to the development of OB after lung transplantation.