Simvastatin improves survival and reduces leukocyte recruitment and hepatocyte apoptosis in endotoxin-induced liver injury

BACKGROUND. Endotoxemia provokes excessive host response to bacteria or microbial compounds, resulting in systemic inflammation, organ injury and mortality. Aim: This study examined the effects of simvastatin on survival and liver injury in endotoxic shock in a rat model of endotoxemia. METHODS. Male Wistar rats were injected intraperitoneally with E.coli-lipopolysaccharide (LPS) and the medial lethal dose (LD50) was determined. Simvastatin was given orally (5-40 mg/kg body weight) for five days prior to either a single LD50 dose of LPS or 2, 2.5 or 3x LD50. Liver damage was assessed by histological examination and expressed as a tissue damaged score (TDS). Another group of rats was treated with simvastatin and then challenged with LPS to determine the degree of apoptosis in hepatocytes, liver immune cells, and cleaved caspase-3 activity after 24h of endotoxemia. RESULTS. Endotoxemia caused substantial mortality with associated leukocyte infiltration, liver injury (TDS = 3.67, SD = 0.55), as well as notable apoptosis of hepatocytes and resident liver macrophages. Simvastatin, in a dose-dependent manner significantly reduced LPS-induced mortality, hepatocellular damage (TDS = 1.5, SD = 0.55), inflammatory infiltration, and dte drug markedly decreased apoptosis and expression of cleaved caspase-3. CONCLUSIONS. Simvastatin improves survival in endotoxic shock and prevents endotoxemic liver injury by inhibiting leukocyte infiltration and hepatocellular apoptosis. These results suggest that simvastatin could be used to prevent endotoxemia-associated liver dysfunction by simvastatin.