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 ( ). 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%, ). In conclusion, JNK2 contributes to MPT-mediated liver injury after H/R. 1. Introduction Multiple trauma is the principal cause of hemorrhagic shock and is typically the consequence of traffic accidents, falls, and, in time of war, casualties of combat [1, 2]. After hemorrhagic shock, resuscitation can lead to multiple organ dysfunction syndrome (MODS), which remains the most significant contributor to late mortality and intensive care unit resource utilization in critical care medicine [3, 4]. The liver is quite vulnerable to injury after ischemia and reperfusion (I/R). After I/R, hepatic necrosis is the predominant mode of cell death, whereas apoptosis is of less importance [5–7]. However, apoptosis and necrosis share common pathways, particularly the mitochondrial permeability transition (MPT) [8]. The MPT is caused by opening of high conductance MPT pores in the mitochondrial inner membrane, which leads to mitochondrial depolarization, uncoupling of oxidative phosphorylation, and large amplitude mitochondrial swelling [9]. The MPT plays a prominent role in the pathogenesis of cell death after I/R injury and a variety of other stresses [9–12]. After onset of the MPT, necrotic cell killing (oncosis) can occur as a consequence of ATP depletion, whereas swelling
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