BACKGROUND: Oxidative stress associated with hemorrhagic shock and reperfusion (HSR) results in the production of superoxide radicals and other reactive oxygen species, leading to cell damage and multiple-organ dysfunction. We sought to determine if MitoQ, a mitochondria-targeted antioxidant, reduces morbidity in a rat model of HSR by limiting oxidative stress. METHODS: HSR was achieved in male rats by arterial blood withdrawal to a mean arterial pressure of 25 ± 2 mm Hg for 1 hour before resuscitation. MitoQ (5 mg/kg), TPP (triphenylphosphonium, 5 mg/kg) or saline (0.9% vol./vol.) was administered intravenously 30 minutes before resuscitation, followed by an intraperitoneal administration (MitoQ, 20 mg/kg) immediately after resuscitation (n = 5 per group). Morbidity was assessed based on cumulative markers of animal distress (0-10 scale). Rats were sacrificed 2 hours after procedure completion, and liver tissue was collected and processed for histology or assayed for lipid peroxidation (thiobarbituric acid reactive substance [TBARS]) or endogenous antioxidant (catalase, glutathione peroxidase [GPx], and superoxide dismutase) activity. RESULTS: HSR significantly increased morbidity as well as TBARS and catalase activities versus sham. Conversely, no difference in GPx or superoxide dismutase activity was measured between sham, HSR, and TPP, MitoQ administration reduced morbidity versus HSR (5.8 ± 0.3 vs. 7.6 ± 0.3; p < 0.05), while TPP administration significantly reduced hepatic necrosis versus both HSR and HSR-MitoQ (1.2 ± 0.1 vs. 2.0 ± 0.2 vs. 1.9 ± 0.2; p < 0.05, n = 5). Analysis of oxidative stress demonstrated increased TBARS and GPx in HSR-MitoQ versus sham (12.0 ± 1.1 μM vs. 6.2 ± 0.5 μM and 37.9 ± 3.0 μmol/min/mL vs. 22.9 ± 2.7 μmol/min/mL, TBARS and GPx, respectively, n = 5; p < 0.05). Conversely, catalase activity in HSR-MitoQ was reduced versus HSR (1.96 ± 1.17 mol/min/mL vs. 2.58 ± 1.81 mol/min/mL; n = 5; p < 0.05). Finally, MitoQ treatment decreased tumor necrosis factor α (0.66 ± 0.07 pg/mL vs. 0.92 ± 0.08 pg/mL) and interleukin 6 (7.3 ± 0.8 pg/mL vs. 11 ± 0.9 pg/mL) versus HSR as did TPP alone (0.58 ± 0.05 pg/mL vs. 0.92 ± 0.08 pg/mL; 6.7 ± 0.6 pg/mL vs. 11 ± 0.9 pg/mL; n = 5; p < 0.05). CONCLUSION: Our data demonstrate that MitoQ treatment following hemorrhage significantly limits morbidity and decreases hepatic tumor necrosis factor α and interleukin 6. In addition, MitoQ differentially modulates oxidative stress and hepatic antioxidant activity.
BACKGROUND: Oxidative stress associated with hemorrhagic shock and reperfusion (HSR) results in the production of superoxide radicals and other reactive oxygen species, leading to cell damage and multiple-organ dysfunction. We sought to determine if MitoQ, a mitochondria-targeted antioxidant, reduces morbidity in a rat model of HSR by limiting oxidative stress. METHODS: HSR was achieved in male rats by arterial blood withdrawal to a mean arterial pressure of 25 ± 2 mm Hg for 1 hour before resuscitation. MitoQ (5 mg/kg), TPP (triphenylphosphonium, 5 mg/kg) or saline (0.9% vol./vol.) was administered intravenously 30 minutes before resuscitation, followed by an intraperitoneal administration (MitoQ, 20 mg/kg) immediately after resuscitation (n = 5 per group). Morbidity was assessed based on cumulative markers of animal distress (0-10 scale). Rats were sacrificed 2 hours after procedure completion, and liver tissue was collected and processed for histology or assayed for lipid peroxidation (thiobarbituric acid reactive substance [TBARS]) or endogenous antioxidant (catalase, glutathione peroxidase [GPx], and superoxide dismutase) activity. RESULTS: HSR significantly increased morbidity as well as TBARS and catalase activities versus sham. Conversely, no difference in GPx or superoxide dismutase activity was measured between sham, HSR, and TPP, MitoQ administration reduced morbidity versus HSR (5.8 ± 0.3 vs. 7.6 ± 0.3; p < 0.05), while TPP administration significantly reduced hepatic necrosis versus both HSR and HSR-MitoQ (1.2 ± 0.1 vs. 2.0 ± 0.2 vs. 1.9 ± 0.2; p < 0.05, n = 5). Analysis of oxidative stress demonstrated increased TBARS and GPx in HSR-MitoQ versus sham (12.0 ± 1.1 μM vs. 6.2 ± 0.5 μM and 37.9 ± 3.0 μmol/min/mL vs. 22.9 ± 2.7 μmol/min/mL, TBARS and GPx, respectively, n = 5; p < 0.05). Conversely, catalase activity in HSR-MitoQ was reduced versus HSR (1.96 ± 1.17 mol/min/mL vs. 2.58 ± 1.81 mol/min/mL; n = 5; p < 0.05). Finally, MitoQ treatment decreased tumor necrosis factor α (0.66 ± 0.07 pg/mL vs. 0.92 ± 0.08 pg/mL) and interleukin 6 (7.3 ± 0.8 pg/mL vs. 11 ± 0.9 pg/mL) versus HSR as did TPP alone (0.58 ± 0.05 pg/mL vs. 0.92 ± 0.08 pg/mL; 6.7 ± 0.6 pg/mL vs. 11 ± 0.9 pg/mL; n = 5; p < 0.05). CONCLUSION: Our data demonstrate that MitoQ treatment following hemorrhage significantly limits morbidity and decreases hepatic tumor necrosis factor α and interleukin 6. In addition, MitoQ differentially modulates oxidative stress and hepatic antioxidant activity.
Authors: Carolyn O Dirain; Maria Raye Ann V Ng; Bailey Milne-Davies; Jerin K Joseph; Patrick J Antonelli Journal: Otol Neurotol Date: 2018-01 Impact factor: 2.311