Endotoxemia is associated by dysregulated apoptosis of immune and non-immune cells. We investigated whether simvastatin has anti-apoptotic effects, and induces hepatocytes and lymphocytes survival signaling in endotoxin-induced liver and spleen injuries. Wistar rats were divided into the groups pretreated with simvastatin (20 or 40 mg/kg, orally) prior to a non-lethal dose of lipopolysaccharide (LPS), the LPS group, and the control. The severity of tissue inflammatory injuries was expressed as hepatic damage scores (HDS) and spleen damage scores (SDS), respectively. The apoptotic cell was detected by TUNEL (Terminal deoxynucleotidyl transferase dUTP Nick End Labeling) and immunohistochemical staining (expression of cleaved caspase-3, and anti-apoptotic Bcl-xL, survivin and NF-κB/p65). Simvastatin dose-dependently abolished HDS and SDS induced by LPS (p < 0.01), respectively. Simvastatin 40 mg/kg significantly decreased apoptotic index and caspase-3 cleavage in hepatocytes and lymphocytes (p < 0.01 vs. LPS group, respectively), while Bcl-XL markedly increased accordingly with simvastatin doses. In the simvastatin, groups were determined markedly increased cytoplasmic expression of survivin associated with nuclear positivity of NF-κB, in both hepatocytes and lymphocytes (p < 0.01 vs. LPS group). Cell-protective effects of simvastatin against LPS seemed to be mediated by up-regulation of survivin, which leads to reduced caspase-3 activation and inhibition of hepatocytes and lymphocytes apoptosis.

Department of Chemistry Faculty of Science University of Hradec Králové Hradec Králové Czechia

Department of Experimental Toxicology and Pharmacology National Poison Control Center Military Medical Academy Belgrade Serbia

Department of Neurology Charles University Prague Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove Czechia

Department of Pharmacology Toxicology and Clinical Pharmacology Faculty of Medicine University of Banja Luka Banja Luka Bosnia and Herzegovina

Institute of Pathology University Clinical Center of Republic of Srpska Faculty of Medicine University of Banja Luka Banja Luka Bosnia and Herzegovina

Malaysia Japan International Institute of Technology Universiti Teknologi Malaysia Kuala Lumpur Malaysia

Medical Faculty of the Military Medical Academy University of Defense in Belgrade Belgrade Serbia

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