Oxidative stress markers (4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine) were increased in LPS-treated animals; CoPP treatment ablated these alterations. An inhibitor for the opening of mitochondrial permeability transition pore, cyclosporine A, suppressed oxidative

stress as well as liver damage during LPS administration. CoPP promoted autophagy and prevented rats from liver damage during LPS administration. Conclusion:  HO-1 promotes autophagy and elimination of damaged mitochondria thereby repressing oxidative stress in LPS-treated rat liver, revealing a novel mechanism for protection by HO-1 against septic liver damage. SEPSIS IS CAUSED by severe infection and is clinically characterized by a systemic inflammatory response, buy Ipilimumab cardiovascular dysfunction, and a precipitous drop in blood Selisistat research buy pressure that leads to multiple organ failure and eventual death.1,2 Recent progress has

indicated that mitochondrial dysfunction is a crucial event during septic shock.3 In addition, recent reports have also indicated a protective role for heme oxygenase-1 (HO-1).4,5 The cytoprotective roles of HO-1 against oxidative stresses have been demonstrated under various pathological conditions including the infection of hepatocytes by hepatitis C.6 Autophagy is a cellular defense system involved in the recycling of proteins during fasting Baricitinib and in the elimination of damaged organelles under pathological conditions.7–10 Septic shock elicited by lipopolysaccharide (LPS) administration causes oxidative stresses in the liver through reducing endogenous antioxidants11 or other mechanisms. Autophagy is induced by LPS in the cardiomyocytes to reduce oxidative stresses and subsequent cellular injuries,12 but the effect of HO-1 induction on LPS-induced autophagy in the

liver has not been examined. THE ANIMAL EXPERIMENTATION protocols used in this study were approved by the Institutional Animal Care and Use Committee of University of Tokyo. Five-week-old male Sprague–Dawley rats were injected i.p. with 15 mg/kg LPS (from Escherichia coli obtained from Sigma [L-2630; St Louis, MO, USA]) dissolved in 0.5 mL isotonic NaCl, or vehicle (n = 4/group). To determine if mitochondrial damage following LPS administration is attenuated by HO-1, an inducer of this enzyme, cobalt protoporphyrin (CoPP [Sigma], 1.5 mg/kg in 0.5 mL dimethylsulfoxide) was injected s.c. into the rats for 4 days consecutively at 24-h intervals. LPS was injected 24 h after the last round of CoPP injection. The animals in the control group received vehicle injections at the same intervals (n = 4/group). Cyclosporin A (CysA, 5 mg/kg) was injected 2 h before the treatment with LPS.