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 relationships between organ transplantation and NO synthesis are unknown, While a number of in vitro and in vivo models have demonstrated an immunomodulatory role for NO, results suggest both an immunosuppressive and immunostimulatory function. In order to better delineate the role of NO in liver transplantation, the Kamada model of rat OLT with strain combinations simulating acute rejection and spontaneous hyporesponsiveness was chosen. In this setting, both acute rejection and spontaneous hyporesponsiveness were associated with increased levels of plasma NO metabolites and allograft expression of the enzyme, NO synthase (iNOS). The extent of expression was significantly greater with acute rejection. Using in situ hybridization, iNOS mRNA was localized to both infiltrating inflammatory cells and hepatocytes in the context of acute rejection, In contrast, iNOS mRNA expression was isolated to the hepatocytes in the hyporesponsive state. To specifically delineate the role of hepatocyte-derived NO, NO synthesis was ablated in the spontaneous hyporesponsiveness model and resulted in significant elevation of serum transaminase values with accompanying histologic evidence of increased periportal inflammatory infiltration. Our results suggest that the site of NO production varies according to the immunologic status of the liver allograft, and hepatocyte-derived NO may be protective in the hyporesponsive state.