The Relationship Between Apoptosis And Inducible Nitric Oxide Synthase (iNOS) On Acute Cardiac Allograft Rejection

Objectives:As the most effective therapy for end-stage heart disease, heart transplantation has been widely used in many medical centers. But the graft rejection, both acute and chronic rejection, is still an obstacle for heart transplantation. How to control the graft rejection is the key to heart transplantation. There is a large body of data concerning the immunologic reactions that cellular and biochemical mechanisms responsible for contractile failure and for the death of cardiac myocytes during cardiac allograft rejection are incompletely understood. T lymphocyte-mediated cytotoxicity and delayed-type hypersensitivity are the major immune mechanisms of cellular allograft rejection. Data suggest that both cell necrosis and apoptosis happen during cardiac allograft rejection. There are other data suggest that apoptosis during rejection parallels to expression of iNOS, Which suggests that apoptosis may be triggered by NO and peroxynitrite. There is few article about blocking iNOS production and see the result. The objective of the present study was to investigate in the rat heart transplantation model the effects of administration of this selective iNOS-blocking drug (aminiguanidine,AG) on the cell apoptosis and histopathology of acute cardiac allograft rejection. Methods:Adult healthy clean inbred strain closed colony rat are chosen, the range of theirweight was 280+ 10g. A rat heterotopic cardiac transplant model with SD donors and Wistar recipients was used. Group A: Wistar to Wistar rat heart transplantation, treated with physiological saline(lml) subcutaneously once daily; Group B: SD to Wistar rat heart transplantation, treated with physiological saline(lml) subcutaneously once daily; GroupC: SD to Wistar heart transplantation and treated with aminiguanidine (AG) subcutaneously once daily. In each group the transplanted hearts were harvested on day3 day5 and day7 respectively, iNOS activity of grafts and apoptosis was detected, histological grade of acute rejection was also examined. Results analysis:The results were analysized by SPSS 10.0 on computer, data are expressed as mean + SEM unless otherwise indicate, with a P <0.05 considered statistically significant. Results:1. Histopathological change of transplanted heart:In control group the cardiac tissue were nearly normal, only rare infiltration of lymphocytes were found. In group B there were a few of lymphocytes infiltrated in and the cardiac tissue were also normal on day3, but on day5 there were much more lymphocytes infiltrated in, myocardium stromal edema and tissue necrosis can be found. On day 7, there were diffused lymphocytes infiltration, stromal edema and a great deal of myocytes necrosis. The change of day3 had no statistic difference compared with Group A (P =0.24), While on day5 and day7, there were significant statistical differences compared with Group A (P <0.01). In group C, the injury of grafts at each time were relived significant by preconditioning with AG compared with Group B (P <0.05), but more serious than Group A(P <0.05).2. the apoptotic cells in cardiac allograft rejection:The apoptotic index parallels the severity of grades of the cardiac allograft rejection.3. INOS activity in each group at each time:On day3, iNOS activity in acute allograft rejection Group B are higher than Group A and Group C (P <0.01), no statistic difference between Group A and GroupC(p >0.05). On day5 after transplantation, iNOS activity in acute allograft rejection Group B are higher than Group A and Group C (P <0.01), no statistic difference between Group A and Group C(P >0.05). On day7, there were significant statistical differences between Group A and Group B, Group B and Group C (P <0.01), no statistic difference between Group A and Group C (P >0.05). Conclusion:1.Characteristics of cardiac tissue injury during acute graft rejection after rat heart transplantation include: lymphocyte infiltration, stromal edema and myocardium necrosis and apoptosis, which can be relived by preconditioning with A...