PRAVASTATIN INCREASES SURVIVAL AND INHIBITS NATURAL-KILLER-CELL ENHANCEMENT FACTOR IN LIVER TRANSPLANTED RATS

Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibit or, has been shown to decrease the number of acute rejection episodes in cardiac and renal transplant patients. This study evaluates the eff ects of pravastatin on survival of rats following liver transplant and attempts to elucidate the mechanisms of these effects. Both survival and natural killer cell enhancing factor (NKEF) studies utilized Dark Agouti rats for donor livers transplanted into Brown Norway rats as re cipients. All rats received daily low-dose cyclosporine (CsA) 2 mg/kg/ day by gavage, The treated groups also received gavage doses of pravas tatin, 20 mg/kg/day. Survival data were analyzed by the method of Kapl an-Meier and log-rank chi(2) tests for statistical significance. For N KEF evaluation, rats were sacrificed at varying time points; total RNA was extracted from the liver and hybridized with P-32-radiolabeled NK EF DNA probes in the Northern blot technique. Radiographs were quantit ated using densitometry. Data were analyzed by two-way ANOVA. Actuaria l survival was improved (P much less than 0.05) in rats treated with p ravastatin in addition to low-dose CsA (n = 41, CsA alone n = 74). Les s fibrosis and chronic rejection was seen on histological section in t he treated animal livers, P < 0.05. NKEF was seen maximally at Days 5- 15 tapering off at Day 21. NKEF-a and NKEF-b levels were significantly decreased in the animals treated with CsA and pravastatin compared to CsA alone in the group of animals < 16 days postop (P much less than 0.05). Pravastatin improves survival in rats following OLT and while t he mechanism is still unknown, inhibition of natural killer cell enhan cement factor may represent an alteration in the overall immune respon se. (C) 1997 Academic Press.