AEROSOL CYCLOSPORINE PREVENTS ACUTE ALLOGRAFT-REJECTION IN EXPERIMENTAL LUNG TRANSPLANTATION

Background: The incidence of acute rejection and the morbidity of syst emic cyclosporine (INN: ciclosporin) after lung transplantation is sig nificant, Experimental evidence suggests that the allograft locally mo dulates the immune mechanisms of acute rejection, The purpose of this study was to determine whether aerosolized cyclosporine would prevent acute cellular rejection, achieve effective graft concentrations with low systemic drug delivery, and locally affect production of the infla mmatory cytokines involved in acute rejection, Methods: Unilateral ort hotopic left lung transplantation was performed in 64 rats (ACI to Lew is), which were divided into eight groups (each group, n = 8): group A , no treatment; groups B to D, aerosol cyclosporine 1 to 3 mg/kg per d ay, respectively; groups E to H, systemic cyclosporine 2, 5, 10, and 1 5 mg/kg per day, respectively, After the animals were killed on postop erative day 2, 4, or 6, the transplanted lung, native lung, spleen, an d blood were collected, Histologic studies, high-pressure liquid chrom atography for trough cyclosporine concentrations, and reverse-transcri ptase polymerase chain reaction for cytokine gene expression were perf ormed, Results: Untreated animals showed grade 4 rejection by postoper ative day 6, Aerosol cyclosporine prevented acute rejection in a dose- dependent fashion, with group D animals (3 mg/kg per day) showing mini mal grade I changes, Among animals receiving systemic cyclosporine, on ly group H (15 mg/kg per day) controlled (grade 1) rejection, However, aerosol cyclosporine, at an 80% lower dose, achieved significantly lo wer concentrations of cyclosporine in the graft (12,349 vs 28,714 ng/m g, p = 0.002004) and blood (725 vs 3306 ng/ml, p = 0.000378). Group F (systemic 5 mg/kg per day) had higher cyclosporine concentrations in t he blood than group D (p = 0.004572) and similar tissue concentrations (p = 0.115180), yet had grade 2 rejection, Reverse-transcriptase poly merase chain reaction demonstrated equivalent suppression of inducible nitric oxide synthase but a 20- to 25-fold higher expression of inter leukin-6, interleukin-10, and interferon-gamma in group D versus group H recipient allografts, Conclusion: Local delivery of cyclosporine by aerosol inhalation dose-dependently prevented acute pulmonary allogra ft rejection, Effective graft levels and low systemic drug delivery re quired significantly lower doses than systemic therapy alone, The gene expression of proinflammatory cytokines involved in allograft rejecti on was suppressed by aerosol cyclosporine therapy.