Differential effects of cyclosporin A and tacrolimus on the production of TGF-beta: implications for the development of obliterative bronchiolitis after lung transplantation.

The development of obliterative bronchiolitis is a common cause for failure of lung allografts. Fibrinogenesis can occur for a number of different reasons but some groups have suggested that cyclosporin A (CsA) and tacrolimus (FK506) have different effects on the cytokines which induce fibrinogenesis. We investigated the effect of tacrolimus and CsA in tissue culture and found that there was indeed a negative effect on human lung small airway epithelial cell proliferation by recombinant transforming growth factor-beta (TGF-beta), which was reversed by anti-TGF-beta. The same effect was seen with CsA at immunosuppressive concentrations, which was also reversed by anti-TGF-beta, whereas no such inhibition was seen with tacrolimus at immunosuppressive doses unless high concentrations were used. Free TGF-beta was confirmed as being elevated in the supernatant of cell culture wells with standard dose CsA as opposed to low dose CsA or tacrolimus using an ELISA assay.