JNK mediates hepatic ischemia reperfusion injury

Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury

“…3C), consistent with the coexistence of oncotic necrosis and apoptotic cell death. 7,8 Importantly, imipramine pretreatment protected the liver against I/R injury, as seen by ALT levels, histology, and TUNEL staining, whereas NOE enhanced the extent of hepatic injury (Fig. 3A-C).…”

“…6 Animal survival was determined using a model of total hepatic ischemia in male wild-type mice (25-30 g), in which only the ischemic tissue is left in place. 7 Control animals were sham operated. See Supplementary Materials and Methods for detailed protocols and treatments.…”

“…[1][2][3][4] Molecular events include nuclear factor kappaB (NF-B) activation, tumor necrosis factor (TNF) generation, JNK activation, mitochondrial permeability transition (MPT), and reactive oxygen species overproduction. [5][6][7][8] Sphingolipids, ceramide in particular, have emerged as signaling lipid intermediates that play a role in the stress response, and as mediators of apoptosis and autophagic cell death (type II programmed cell death). [9][10][11][12] Ceramide levels in cells can increase by de novo synthesis in the endoplasmic reticulum from the N-acylation and subsequent desaturation of sphinganine.…”

Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

“…These results also suggest that other events such as activation of the cell death-related JNK and/or p38 kinase likely occur and accelerate severe tissue damage. [10][11][12][13] Numerous mitochondrial proteins involved in energy supply and electron transport system, molecular chaperone activity, anti-oxidant defense, the urea cycle, degradation of fatty acids, etc, have been simultaneously oxidized and S-nitrosylated (Fig. 4 and Table 1) during I/R injury, as observed in ethanol-exposed animals, 23 often leading to decreased activity/function.…”

“…9 Both elevated ROS/RNS and pro-inflammatory cytokines such as TNFα also activate various cell death signaling pathways via c-Jun, N-terminal kinase (JNK) 10-12 and p38 kinase, 12,13 leading to apoptosis and/or necrosis. 10,11,[14][15][16][17][18] Consistent with the importance of these pathways, a variety of pharmacological agents such as specific JNK inhibitors 11 and various antioxidants (e.g. ascorbate, glutathione, S-adenosylmethionine, vitamine E, etc.)…”