Inhibition of inducible nitric oxide synthase prolongs rat lung allograft survival

Nitric oxide (NO) has been demonstrated to be an important immunoregulation molecule in the process of cellular immunologic interactions. Our recent results demonstrated that NO is produced in association with acute allograft rejection and NO inhibition may suppress rejection histologically. This data provides direct evidence of NO in allograft rejection and the immunosuppressive potential of NO inhibitors. In this paper, the effect of NO inhibition on allograft survival was evaluated to investigate the capacity of NO inhibitors as immunosuppressive agents. Seventeen rat left lung transplants from BN donors to F344 recipients were accepted for this study. After surgery, recipients were randomized into two groups and received either aminoguanidine (AG), a highly selective NO synthase inhibitor, 200 mg/kg, intra-peritoneal every 6h (n = 13) or normal saline treatment (n = 4). No production was determined from the recipient's serum nitrite and nitrate levels. Graft survival was monitored via semi-quantitative radiographic aeration scores (AS: 0 = opaque lung to 6 = normal appearing lung). The nitrite and nitrate levels were clearly detectable before the radiographic finding associated with rejection became obvious. Production of NO was significantly inhibited by AG treatment. AG treatment prolonged allograft survival radiographically (12.0 days and 6.0 days for treated and untreated groups respectively, p = 0.0001). These data suggest that the inducible NO is produced in association with acute lung allograft rejection and may serve as a sensitive rejection marker. NO inhibition significantly prolonged rat lung allograft survival but failed to induce immunological tolerance.