Protective Effects Of Blocking The Pathhway Of NF-κB On Liver Injury After Intestinal Ischemia/Reperfusion

Intestinal ischemia/reperfusion injury (Ⅱ/R) is a pathophysiologic process happened frequently during the therapy of many diseases such as serious trauma and shock and may result in many serious complications. It is also an important factor of genesis and development of MODS. Ischemia-reperfusion injury of the intestine not only hurts the intestines but also causes the remote organs such as lung and liver failure. The transcription factor nuclear factor kappaB (NF-kappaB) can regulate transcription and expression of many inflammatory mediators. It has been reported that nuclear factor kapp(aNF–κB )activated during the acute liver injury.Pyramiding dithiocarbamate(PDTC)is an antioxidant,acting as an inhibitor of NF–κB can prevent the liver injury induced byⅡ/R through inhibiting the activity of NF–κB.AIM: In this study, we examined whether blocking the pathway of NF–κB had protective effect on liver injury after intestinal ischemia/reperfusion and observed the influence of PDTC as an inhibitor of NF-κB on the activity of NF–κB, adhesion of neutrophilic granulocyte, lipid peroxidation and the content of TNF-α. Furthermore we will explore its protective mechanism.METHODS AND RESULTS:Twenty-four male Wistar rats weighing 200~240 g were randomly assigned into three groups as follows: (1) control group: sham operation group (2) I/R group: intestinal ischemia/reperfusion injury was induced by clamping the mesentery artery 1 hour and then the clip was removed initiating intestinal reperfusion 2 hours. (3) PDTC (100mg/kg) pretreatment group. Briefly, 1 h before the induction of ischemia rats received intraperitoneal injection PDTC (100mg/kg, for PDTC group).In the sham group,SAM was only isolated without clamping. Blood sample,liver tissue samples were collected after reperfusion 2 hours. The histology of liver was observed,alanine aminotransferase(ALT), aspartate aminotransferase( AST), and serum level of tumor necrosis factor–a(TNF-a),and liver superoxide dismutase(SOD),nitrete/nitrate(NO)were measured. The immunohhistochemical expressions of liver NF-kB and P-selectin were performed.RESULTS:Ⅱ/R induced liver injury characterized by the histological evidence of liver edema,hemorrhage, polymorphonuclear neutrophi(lPMN)infiltration and elevated serum levels of AST and ALT. Serum TNF-a level was significantly higher than that of control group(p<0.01)and the liver oxidant product were observed in high level (p<0.01),these changes were parallel to the positive expressions of NF–κB and ICAM-1.After administration of PDTC, the histological evidence of liver injury was improved,the levels of P-selectin and NF-kB were weakened.CONCLUSION:Ⅱ/R may result in apparent liver damage, the mechanism may be involved of oxidation injury , polymorphonuclear nvtrophils( PMN) accumulation and elevated cytokines mediators .The mechanism of liver injury induced by II/R is complicated which has relation to the activation of NF–κB . PDTC,an agent known to inhibit the activation of NF–κB ,can reduce and prevent this kind of liver injury.