Effect of antioxidants on the renal expression of cytokines, inos, adhesion molecules and mhc antigens in a syngeneic renal transplant model: Testing the "response-to-injury" hypothesis

In aTecent clinical study antioxidant therapy at the lime of renal transplantation was associated with fewer rejection and extended graft survival. A hypothesis generated by such studies and based on the "response-to-injury" model is that reducing the oxidative injury may dampen certain cellular responses to injury, important in triggering allograft rejection. To test if ablation of oxidative injury would limit such responses, kidneys were transplanted between Furth-Wistar rats with antioxidant 21-aminosteroid (n=7) or its vehicle (n=7). 21Aminosteroid (6 mg/kg) or the vehicle was injected into the donor prior to the kidney harvest. The kidney-flushed and cold-preserved for 24 hours in UW solution-was transplanted with the infusion of 21-aminosteroid (3 mg/kg) or vehicle just prior to reperfusion. The normal kidneys removed from the recipients to make room for the transplanted kidneys were used as normal control kidneys. The kidney contralateral to the transplanted kidney was removed on day 4 and transplant nephrectomy was carried out on day 7. Antioxidant therapy was attended by inhibition of lipid peroxidation (renal malondialdehyde: 0. 37±0. 04 Vs. 0. 20ifl. 03 nmol/mg protein, p<0. 05) and improved kidney function (S Cr: 2. 8+0. 2 Vs. 1. 9+0. 2 mg/dl, P<0. 05). Cytokine mRNA expression by RT-PCR was increased in the transplanted kidney for IL-2 and IL-6 to 3. 3 fold, IFN-y to 2. 4 fold and TNF-cc to 1. 6 fold. mRNA for IL-1 and IL-6 was same as in the normal control kidney. All these cytokines were either suppressed or attenuated with 21-aminosteroid therapy. A 40 fold increase in iNOS mRNA in the transplanted kidney was completely inhibited by 21aminosteroid. ICAM-I, VCAM-I, ELAM-I and MHC I and II antigen expression by immunocytochemical methods was strong in the transplanted kidneys and appeared to have been unaffected by 2î-aminosteroid therapy. That transplantation-related injury-in the absence of alloreactivity-invokes cytokine, iNOS, MHC antigenic and adhesion molecular responses and that antioxidant therapy limits some of these responses provide partial supports for the "response-to-injury" hypothesis in the transplant setting.