scholarly journals C-Jun N-Terminal Kinase 2 Promotes Liver Injury via the Mitochondrial Permeability Transition after Hemorrhage and Resuscitation

HPB Surgery ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Christoph Czerny ◽  
Tom P. Theruvath ◽  
Eduardo N. Maldonado ◽  
Mark Lehnert ◽  
Ingo Marzi ◽  
...  
Keyword(s):  
Liver Injury ◽  
Intravital Microscopy ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Hepatic Necrosis ◽  
Sham Operation ◽  
Shed Blood ◽  
Mitochondrial Permeability ◽  
Lactated Ringer's Solution ◽  
Mitochondrial Staining

Hemorrhagic shock leads to hepatic hypoperfusion and activation of mitogen-activated stress kinases (MAPK) like c-Jun N-terminal kinase (JNK) 1 and 2. Our aim was to determine whether mitochondrial dysfunction leading to hepatic necrosis and apoptosis after hemorrhage/resuscitation (H/R) was dependent on JNK2. Under pentobarbital anesthesia, wildtype (WT) and JNK2 deficient (KO) mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer’s solution. Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation. Mitochondrial polarization was assessed by intravital microscopy. After H/R, ALT in WT-mice increased from 130 U/L to 4800 U/L. In KO-mice, ALT after H/R was blunted to 1800 U/l (P<0.05). Necrosis, caspase-3 activity and ROS were all substantially decreased in KO compared to WT mice after H/R. After sham operation, intravital microscopy revealed punctate mitochondrial staining by rhodamine 123 (Rh123), indicating normal mitochondrial polarization. At 4 h after H/R, Rh123 staining became dim and diffuse in 58% of hepatocytes, indicating depolarization and onset of the mitochondrial permeability transition (MPT). By contrast, KO mice displayed less depolarization after H/R (23%, P<0.05). In conclusion, JNK2 contributes to MPT-mediated liver injury after H/R.

scholarly journals Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice

2014 ◽  
Vol 306 (4) ◽  
pp. G265-G277 ◽  
Author(s):  
Adrienne L. King ◽  
Telisha M. Swain ◽  
Zhengkuan Mao ◽  
Uduak S. Udoh ◽  
Claudia R. Oliva ◽  
...  
Keyword(s):  
Liver Injury ◽  
Light Chain ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Ethanol Consumption ◽  
Liver Mitochondria ◽  
Chronic Ethanol ◽  
Mitochondrial Permeability ◽  
Chronic Ethanol Consumption ◽  
Microtubule Protein

Chronic ethanol consumption increases sensitivity of the mitochondrial permeability transition (MPT) pore induction in liver. Ca2+ promotes MPT pore opening, and genetic ablation of cyclophilin D (CypD) increases the Ca2+ threshold for the MPT. We used wild-type (WT) and CypD-null (CypD−/−) mice fed a control or an ethanol-containing diet to investigate the role of the MPT in ethanol-mediated liver injury. Ca2+-mediated induction of the MPT and mitochondrial respiration were measured in isolated liver mitochondria. Steatosis was present in WT and CypD−/− mice fed ethanol and accompanied by increased terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive nuclei. Autophagy was increased in ethanol-fed WT mice compared with ethanol-fed CypD−/− mice, as reflected by an increase in the ratio of microtubule protein 1 light chain 3B II to microtubule protein 1 light chain 3B I. Higher levels of p62 were measured in CypD−/− than WT mice. Ethanol decreased mitochondrial respiratory control ratios and select complex activities in WT and CypD−/− mice. Ethanol also increased CypD protein in liver of WT mice. Mitochondria from control- and ethanol-fed WT mice were more sensitive to Ca2+-mediated MPT pore induction than mitochondria from their CypD−/− counterparts. Mitochondria from ethanol-fed CypD−/− mice were also more sensitive to Ca2+-induced swelling than mitochondria from control-fed CypD−/− mice but were less sensitive than mitochondria from ethanol-fed WT mice. In summary, CypD deficiency was associated with impaired autophagy and did not prevent ethanol-mediated steatosis. Furthermore, increased MPT sensitivity was observed in mitochondria from ethanol-fed WT and CypD−/− mice. We conclude that chronic ethanol consumption likely lowers the threshold for CypD-regulated and -independent characteristics of the ethanol-mediated MPT pore in liver mitochondria.

scholarly journals Minocycline Decreases Liver Injury after Hemorrhagic Shock and Resuscitation in Mice

HPB Surgery ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Christoph Czerny ◽  
Andaleb Kholmukhamedov ◽  
Tom P. Theruvath ◽  
Eduardo N. Maldonado ◽  
Venkat K. Ramshesh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Mitochondrial Dysfunction ◽  
Intravital Microscopy ◽  
Caspase 3 ◽  
Multiple Organ ◽  
Shed Blood ◽  
Lactated Ringer's Solution ◽  
Liver Homogenates ◽  
And Oxidative Stress

Patients that survive hemorrhage and resuscitation (H/R) may develop a systemic inflammatory response syndrome (SIRS) that leads to dysfunction of vital organs (multiple organ dysfunction syndrome, MODS). SIRS and MODS may involve mitochondrial dysfunction. Under pentobarbital anesthesia, C57BL6 mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer’s solution containing minocycline, tetracycline (both 10 mg/kg body weight) or vehicle. Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation. Mitochondrial polarization was assessed by intravital microscopy. After H/R with vehicle or tetracycline, ALT increased to 4538 U/L and 3999 U/L, respectively, which minocycline decreased to 1763 U/L (P<0.01). Necrosis and TUNEL also decreased from 24.5% and 17.7 cells/field, respectively, after vehicle to 8.3% and 8.7 cells/field after minocycline. Tetracycline failed to decrease necrosis (23.3%) but decreased apoptosis to 9 cells/field (P<0.05). Minocycline and tetracycline also decreased caspase-3 activity in liver homogenates. Minocycline but not tetracycline decreased lipid peroxidation after resuscitation by 70% (P<0.05). Intravital microscopy showed that minocycline preserved mitochondrial polarization after H/R (P<0.05). In conclusion, minocycline decreases liver injury and oxidative stress after H/R by preventing mitochondrial dysfunction.

770 Preconditioning delays Ca2+-induced mitochondrial permeability transition

2003 ◽  
Vol 2 (1) ◽  
pp. 167 ◽  
Author(s):  
L ARGAUD ◽  
O GATEAUROESCH ◽  
D MUNTEAN ◽  
L GOMEZ ◽  
L CHALABREYSSE ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability
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