Pravastatin increases survival and inhibits natural killer cell enhancement factor in liver transplanted rats.
Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown to decrease the number of acute rejection episodes in cardiac and renal transplant patients. This study evaluates the effects 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 recipients. All rats received daily low-dose cyclosporine (CsA) 2 mg/kg/day by gavage. The treated groups also received gavage doses of pravastatin, 20 mg/kg/day. Survival data were analyzed by the method of Kaplan-Meier and log-rank chi 2 tests for statistical significance. For NKEF evaluation, rats were sacrificed at varying time points; total RNA was extracted from the liver and hybridized with 32P-radiolabeled NKEF DNA probes in the Northern blot technique. Radiographs were quantitated using densitometry. Data were analyzed by two-way ANOVA. Actuarial survival was improved (P < < 0.05) in rats treated with pravastatin in addition to low-dose CsA (n = 41, CsA alone n = 74). Less fibrosis and chronic rejection was seen on histological section in the 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 < < 0.05). Pravastatin improves survival in rats following OLT and while the mechanism is still unknown, inhibition of natural killer cell enhancement factor may represent an alteration in the overall immune response.
Kakkis
J L
JL
Department of Surgery, Liver and Pancreas Transplantation, UCLA School of Medicine 90095-7054, USA. jkakkis@surgery.medsch.ucla.edu
Ke
B
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Dawson
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Maggard
M
M
Si
M
M
Kaldas
F
F
Cai
W
W
Shau
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Seu
P
P
Sauri
H
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Busuttil
R W
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Imagawa
D K
DK
D000818:Animals; D001798:Blood Proteins / Q000096:biosynthesis* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects*; D016572:Cyclosporine / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006084:Graft Rejection / Q000473:pathology; D006360:Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation / Q000276:immunology / Q000473:pathology; D010544:Peroxidases; D054464:Peroxiredoxins; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016019:Survival Analysis
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D010544:Peroxidases; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D017035:Pravastatin