The Role Of C-jun-N-Terminal Kinase In Hepatic Ischemia/Reperfusion Injury In Rats

Objective:To investigate the mechanisms of JNK signaling pathway in hepatic ischemia/reperfusion injury and the function of SP600125, a specific and selective JNK inhibitor in alleviating hepatic ischemia /reperfusion injury.This process can accordingly provides a new apotropaic and treating means for hepatic ischemia/reperfusion injury in clinical liver transplantation.Methods:Thirty normal male Sprague-Dawley rats weighting 250-300g were randomly divided into three groups:A:sham operation group (SO),B-ischemia/ reperfusion group (IR) and C:JNK inhibitor SP600125 group (SP).Namely group A was anesthetized with the isolation and exposure of hepatoduodenal ligament,without vascular ligation.In group B,rats were subjected to the isolation and exposure of hepatoduodenal ligament; the blood flow to middle and left lobes was obstructed by artery clamp for an hour.Then,All rats were killed at 2 hours after reperfusion. Rats in Group C were injected with SP600125 (15mg·kg-1).The following parameters were measured:(1)pathological changes in HE staining (2) hepatocellular apotosis index(AI, by TUNEL methods) (3)Expression of P-JNK in liver tissure (by immuno histochemistry methods) (4) levels of ALT,AST (5) contents of maleicdialdehyde (MDA) and myeloPeroxidase(MPO) in liver tissure.(6) the level tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in serum.Results:(1)No significant histopathologically changes were observed in Group SO.Group IR had serious and significant pathologically changes:hepatic lobule was extensively destroyed, infiltrated with inflammatory cell;heptic cell and vascular endothelial cell in blood sinus were high hydropic.While group SP had a lighter Cell degeneration and necrosis than group IR. (2) Hepatocellular apotosis index:litlle hepatocellular apotosis was observed in Group SO. AI in Group IR and group SP were significantly higher than group SO (P＜0.01).While the level of AI in group SP was obviously lower than group IR (P＜0.05). (3) p-JNK was scarcely expressed in group SO.Significant enhanced expessions of p-JNK were shown in group IR and group SP.But in group IR, p-JNK was expressed in both endochylema and nucleus,and also had a deep staining.(4)Compared with group SO,the level of ALT,AST were significantly high in group IR and group SP. However the index in group SP was also significantly lower than group IR.(5) Higher contents of MDA and MPO in group IR Between group IR and group SP, heptatic MDA and MPO in group SP were significantly lower than group IR (P＜0.05). (6) Group IR and group SP had a higher level of TNF-αand IL-1β.But the index in group SP were lower than group IR.Conclusions:(1) In process of hepatic ischemia/reperfusion injury, JNK signaling pathway was extensively activated,p-JNK has a high expression. (2) Hepatic ischemia/reperfusion injury can be alleviated by SP600125.(3)PMN, IL-1β, TNF-αplay a considerable role in hepatic ischemia/reperfusion injury,and may have some relations with JNK signaling pathway.