Differential Relevance of NF-κB and JNK in the Pathophysiology of Hemorrhage/Resususcitation-Induced Liver Injury after Chronic Ethanol Feeding

Abstract

BackgroundChronic ethanol (EtOH) abuse worsens pathophysiological derangements after hemorrhagic shock and resuscitation (H/R) that induce hepatic injury and strong inflammatory changes via JNK and NF-κB activation. Inhibiting JNK with a cell-penetrating, protease-resistant peptide D-JNKI-1 after H/R in mice with healthy livers ameliorated these effects. Here, we studied if JNK inhibition by D-JNKI-1 in chronically EtOH-fed mice after hemorrhagic shock prior to the onset of resuscitation also confers protection.MethodsMale mice were fed a Lieber-DeCarli diet containing EtOH or an isocaloric control (ctrl) diet for 4 weeks. Animals were hemorrhaged for 90 min (32 ± 2 mm Hg) and randomly received either D-JNKI-1 (11 mg/kg, intraperitoneally, i. p.) or sterile saline as vehicle (veh) immediately before the onset of resuscitation. Sham animals underwent surgical procedures without H/R and were either D-JNKI-1 or veh treated. Two hours after resuscitation, blood samples and liver tissue were harvested.ResultsH/R induced hepatic injury with increased systemic interleukin (IL)-6 levels, and enhanced local gene expression of NF-κB-controlled genes such as intercellular adhesion molecule (ICAM)-1 and matrix metallopeptidase (MMP)9. c-Jun and NF-κB phosphorylation were increased after H/R. These effects were further increased in EtOH-fed mice after H/R. D-JNKI-1 application inhibited the proinflammatory changes and reduced significantly hepatic injury after H/R in ctrl-fed mice. Moreover, D-JNKI-1 reduces in ctrl-fed mice the H/R-induced c-Jun and NF-κB phosphorylation. However, in chronically EtOH-fed mice, JNK inhibition did not prevent the H/R-induced hepatic damage and proinflammatory changes nor c-Jun and NF-κB phosphorylation after H/R.ConclusionsThese results indicate, that JNK inhibition is protective only in not pre-harmed liver after H/R. In contrast, the pronounced H/R-induced liver damage in mice being chronically fed with ethanol cannot be prevented by JNK inhibition after H/R and seems to be under the control of NF-κB.

Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia

“…Activation of stress-response kinase JNK, a member of the important MAPK family, is a common feature of alcohol-caused tissue injury ( 20 , 21 ). Other MAPK family members (p38 and extracellular ERK) may also contribute in a cellular context and type-dependent fashion ( 35 – 37 ).…”

“…Stress-activated c-Jun NH( 2 )-terminal kinase (JNK) is activated by many types of stress stimuli such as cardiovascular diseases, aging, and diabetes ( 16 – 19 ). JNK activation is well known to contribute to alcohol-caused organ damage ( 20 , 21 ). We recently reported that JNK activation promotes AF in aged hearts ( 18 , 19 ).…”

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

“…Several studies in vitro, as well as in vivo, proved that JNK inhibitions with D-JNKI1 can offer an intriguing strategy against brain diseases, including excitotoxicity and cerebral ischemia [ 63 ], neuropathic pain [ 138 ], AD [ 139 , 140 ], SMA [ 141 ], deafness [ 142 , 143 ], ocular inflammation [ 144 ], liver injury [ 145 ], spinal cord injury [ 146 ] and traumatic brain injury [ 147 , 148 ]. The disadvantages of using a CPP, which is able to cross all the barriers (BBB) and inhibit all JNK isoforms in the whole body, are the possible side effects.…”

Antifatigue Effects of Antrodia cinnamomea Cultured Mycelium via Modulation of Oxidative Stress Signaling in a Mouse Model

“…The levels of ALT and AST in the serum are considered as a biochemical marker for assessing liver function [26], which were examined to explore effect of AC on hepatic function. Compared to unexercised mice, 60 min swimming failed to influence the levels of ALT and AST in serum ( P > 0.05, F = 0.18–1; Figure 3).…”