C-Jun N-Terminal Kinase 2 Promotes Liver Injury via the Mitochondrial Permeability Transition after Hemorrhage and Resuscitation. (10th April 2012)

• Record Type: Journal Article
• Authors: Czerny, Christoph; Theruvath, Tom P.; Maldonado, Eduardo N.; Lehnert, Mark; Marzi, Ingo; Zhong, Zhi; Lemasters, John J.
• Other Names: Schemmer Peter Academic Editor.
• Is Part Of: HPB surgery. Volume 2012(2012)
• Publication Date: 2012-04-10
• Subjects: Biliary tract -- Surgery -- Periodicals; Liver -- Surgery -- Periodicals; Pancreas -- Surgery -- Periodicals; 617.55
• DOI: 10.1155/2012/641982
• Languages: English
• ISSNs: 0894-8569

Abstract

Abstract : 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.