CELLULAR-LOCALIZATION AND EFFECT OF NITRIC-OXIDE SYNTHESIS IN A RAT MODEL OF ORTHOTOPIC LIVER-TRANSPLANTATION

Nitric oxide (NO) is a multifunctional free radical with a variety of described biochemical and physiological roles, The immunologic relatio nships between organ transplantation and NO synthesis are unknown, Whi le a number of in vitro and in vivo models have demonstrated an immuno modulatory role for NO, results suggest both an immunosuppressive and immunostimulatory function. In order to better delineate the role of N O in liver transplantation, the Kamada model of rat OLT with strain co mbinations simulating acute rejection and spontaneous hyporesponsivene ss was chosen. In this setting, both acute rejection and spontaneous h yporesponsiveness were associated with increased levels of plasma NO m etabolites and allograft expression of the enzyme, NO synthase (iNOS). The extent of expression was significantly greater with acute rejecti on. Using in situ hybridization, iNOS mRNA was localized to both infil trating inflammatory cells and hepatocytes in the context of acute rej ection, In contrast, iNOS mRNA expression was isolated to the hepatocy tes in the hyporesponsive state. To specifically delineate the role of hepatocyte-derived NO, NO synthesis was ablated in the spontaneous hy poresponsiveness model and resulted in significant elevation of serum transaminase values with accompanying histologic evidence of increased periportal inflammatory infiltration. Our results suggest that the si te of NO production varies according to the immunologic status of the liver allograft, and hepatocyte-derived NO may be protective in the hy poresponsive state.