Effect of aminoguanidine and cyclosporine on lung allograft rejection

Aminoguanidine, a nitric oxide synthase inhibitor, has been shown to reduce the inflammatory allogeneic response. Here we used it in combination with cyclosporine to evaluate its effect on a clinically relevant immunosuppressive protocol.

Orthotopic left lung transplantation was performed in 120 rats, of which 24 were syngeneic Lewis to Lewis controls, and allogeneic transplantations were performed across major histoincompatibility barriers (ACI to Lewis). We studied synchronous histologic changes accompanying cytokines and nitric oxide synthase messenger RNA by reverse transcriptase polymerase chain reaction in the grafted lungs. Nitrate/nitrite, oxidized degradation products of nitric oxide, were measured in the whole blood, as were concentrations of cyclosporine. Lung tissue was immunohistochemically stained for nitric oxide synthase protein. Rats receiving allografts were either untreated (24) or received low-dose cyclosporine (232 +/- 105 ng/mL blood by high-performance liquid chromatography), high-dose cyclosporine (2,046 +/- 664 ng/mL), aminoguanidine alone (800 mg. kg-1. day-1 intraperitoneally), or aminoguanidine plus low-dose cyclosporine.

The results suggest that aminoguanidine combined with low doses of cyclosporine can reduce the allogeneic response across major histoincompatibilities in rodent lung transplantation. Its biologic effect may not exclusively depend on the inhibition of nitric oxide synthase and may, by other means, reduce proinflammatory cytokines.

Aminoguanidine may be an effective adjuvant to conventional immunosuppression.