mitoquinone and Sepsis

Sepsis is one of the main causes of death among critically ill patients. Sepsis pathogenesis includes infection by gram-negative and gram-positive bacteria, fungi, or both; exacerbated inflammatory response; hypotension, with potential to cause vasodilatory shock; and lesser delivery of oxygen to tissues due to impairment of oxygen utilization by cells. The participation of reactive species and/or free radicals such as nitric oxide (NO), peroxynitrite (ONOO

Topics: Adenosine Triphosphate; Animals; Antioxidants; Apoptosis; Humans; Melatonin; Mitochondria; Multiple Organ Failure; Necrosis; NF-kappa B; Organophosphorus Compounds; Oxidative Stress; Selenium; Sepsis; Ubiquinone; Vitamins

To investigate the effects of autophagy on exocrine function of pancreas in rats with acute sepsis, and to determine whether the mitochondrial coenzyme Q (Mito Q) can prevent exocrine dysfunction of pancreas mediated by autophagy.. Experiment I: 30 Sprague-Dawley (SD) rats were randomly divided into three groups, with 10 rats in each group. All the rats were given lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally, and Wortmannin (2 mg/kg), the specific inhibitor of autophagy (LPS + Wortmannin group), Mito Q (6.5 μmol/kg, LPS + Mito Q group), or the same volume of normal saline (LPS group) was respectively injected via the tail vein 1 hour later. Survival rate was assessed within 12 hours after LPS injection. Experiment II: another 100 male SD rats were randomly divided into ten groups with 10 rats in each group: namely control 4, 6 and 12 hours groups, LPS 4, 6 and 12 hours groups, and LPS + Wortmannin 4 hours group, Wortmannin 4 hours group, LPS + Mito Q 6 hours group, and Mito Q 6 hours group. The protocols of model reproduction and drug administration were the same as in the experiment I. Blood samples were collected at each time point, and the amylase content was determined with the velocity method. The levels of reactive oxygen species (ROS) in the pancreases were measured with enzyme-linked immunosorbent assay (ELISA). The expression of the autophagy-related protein LC3 was determined with Western Blot. The pathological changes in the pancreas were observed with microscopy.. (1) The survival time in the LPS + Wortmannin group was significantly shorter than that in the LPS group (hours: 7.50±0.64 vs. 11.90±0.13, χ (2) = 19.847, P = 0.001). There was no significant difference in the survival time between LPS + Mito Q and LPS groups (hours: 11.60±0.24 vs. 11.90±0.13, χ (2) = 1.055, P = 0.137). (2) The serum amylase in the LPS 6 hours, LPS + Wortmannin 4 hours, and LPS + Mito Q 6 hours groups were significantly higher than those in the control group at the same time points (U/L: 2 881.00±550.12 vs. 2 099.20±249.57, 3 672.00±779.24 vs. 2 081.36±245.18, 2 975.20±687.03 vs. 2 099.20±249.57, all P < 0.05), and were significantly lowered in LPS 12 hours group (U/L: 794.00±218.71 vs. 2 086.80±261.75, P < 0.01). The pancreatic ROS in the LPS 6 hours and 12 hours groups, LPS + Wortmannin 4 hours group, and LPS + Mito Q 6 hours group were significantly higher than those of the control group at the same time points (kU/L: 3.18±1.06 vs. 1.78±0.37, 3.63±1.08 vs. 1.85±0.41, 3.14±0.98 vs. 1.65±0.34, 3.17±1.03 vs. 1.78±0.37, all P < 0.05). The serum amylase and pancreatic ROS in LPS + Wortmannin 4 hours group were significantly higher than those of the LPS group at the same time points (U/L: 3 672.00±779.24 vs. 2 432.20±442.85, kU/L: 3.14±0.98 vs. 1.87±0.42, both P < 0.05), but there were no differences in above two parameters between LPS + Mito Q 6 hours group and LPS group (U/L: 2 975.20±687.03 vs. 2 881.00±550.12, kU/L: 3.17±1.03 vs. 3.18±1.06, both P > 0.05). Light microscopy showed that obvious pathological changes were found in the pancreas in the LPS 6 hours and 12 hours groups, LPS + Wortmannin 4 hours group, and LPS + Mito Q 6 hours group. Electron microscopy showed that the number of autophagic vacuoles increased 6 hours after LPS administration. There was no difference at any time point in the number of autophagic vacuoles between LPS + Mito Q 6 hours group and LPS 6 hours group, and the autophagic vacuoles were not found after Wortmannin intervention. It was demonstrated by Western Blot that the levels of LC3 protein in the LPS 6 hours and 12 hours groups, and LPS + Mito Q 6 hours group were significantly higher than those of the control group at the same time points (A value: 0.34±0.02 vs. 0.17±0.02, 0.37±0.03 vs. 0.18±0.04, 0.36±0.02 vs. 0.17±0.02, all P < 0.05), but there were no differences between LPS 12 hours group or LPS + Mito Q 6 hours group and LPS 6 hours group (both P > 0.05).. Autophagy prevents exocrine dysfunction of pancreas in septic rats, and the autophagic capacity or autophagosome-formation rate may determine the development of exocrine pancreatic dysfunction. The mitochondria-targeted antioxidant Mito Q does not prevent exocrine dysfunction of pancreas.

Topics: Acute Disease; Androstadienes; Animals; Autophagy; Lipopolysaccharides; Male; Mitochondria; Organophosphorus Compounds; Pancreas, Exocrine; Rats; Rats, Sprague-Dawley; Sepsis; Ubiquinone; Wortmannin

Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage.. Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines.. MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001).. Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis.

Topics: Acute Disease; Animals; Antioxidants; Biomarkers; Cytokines; Escherichia coli; Interleukin-6; Kidney Function Tests; Lipopolysaccharides; Liver Function Tests; Male; Melatonin; Mitochondria; Multiple Organ Failure; Organophosphorus Compounds; Oxidative Stress; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Sepsis; Staphylococcus aureus; Ubiquinone

Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.

Topics: Animals; Antioxidants; Cell Line; Creatinine; Cytokines; Disease Models, Animal; Endothelial Cells; Humans; Interleukin-10; Lipopolysaccharides; Membrane Potential, Mitochondrial; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Peptidoglycan; Rats; Reactive Oxygen Species; Sepsis; Spectrometry, Fluorescence; Ubiquinone