Dual Role Of NF-κB In A Mouse Model Of Intestinal Ischemia-reperfusion Injury

Backgrouds:Intestinal ischemia-reperfusion（I/R）injury is a significant problem in abdominal aortic aneurysm surgery,small bowel or liver transplantation,hepatectomy or pancreatectomy,cardiopulmonary bypass,strangulated hernias and neonatal necrotizing enterocolitis,and also often occurs as a consequence of major stressful events such as burns,trauma,surgery,shock,sepsis,and multiple organ failure.Intestinal I/R rapidly activates local,remote,and systemic inflammatory responses,which contribute substantially to injury of the intestine and in distant organs including the lung,heart,kidney and liver,leading finally to multiple organ failure and death.NF-κB plays a critical role in the regulation of inflammatory and innate immune responses.The role of NF-κB in the pathogenesis of intestinal injury remains a controversial issue at present,with either deleterious or beneficial effects having been reported.Objectives:The present study was designed to examine the role of NF-κB in the mouse model of intestinal I/R-induced mucosal injury and inflammation,to define specifically whether it plays a protective or deleterious role,and to elucidate further the corresponding mechanism.Methods:Severe and mild intestinal I/R injuries were induced by intestinal ischemia with different ischemia duration of 120 min and 50 min followed by reperfusion for 2h with the method of superior mesenteric artery occlusion（SMA）.Intestinal I/R-induced gastric mucosal injury and inflammatory response were examined in wild-type and NF-κB1（p50）knockout mice.Intestinal mucosal injury was assessed by gross and histologic examination.Serum levels of TNF-a,IL-1b,and IL-10 were measured by enzyme-linked immunosorbent assay.Myeloperoxidase（MPO）activity was used as the index of PMNs infiltration in the intestinal mucosa.Nuclear extract isolation and electrophoretic mobility shift assay（EMSA）were performed to examine the activation of NF-κB in intestinal mucosa.Results:NF-κB was rapidly activated following intestinal I/R in intestinal mucosa and the activated NF-κB complexes predominantly involve p50/p65 but also p50/p50.The majority ofκB DNA-binding activity in intestinal mucosa was abrogated from p50^-/-mice during intestinal I/R.Gross and histological examination showed that NF-κB activation plays a protective and injurious role in mucosal injury induced by 120 min and 50 min ischemia with subsequent reperfusion,respectively.ELISA results showed that both serum levels of TNF-aand IL-1bwere significantly decreased,and by contrast,serum IL-10 levels were markedly increased in NF-κB（-/-）mice relative to WT mice when challenged to 120 min-ischemia/reperfusion.On the contrary,when subjected to 50 min-ischemia/reperfusion,serum TNF-aand IL-1bwere significantly increased,and in contrast,IL-10 levels were markedly decreased in NF-κB（-/-）mice compared with WT controls.The mucosal MPO activities were largely decreased and drastically increased in NF-κB（-/-）mice compared with WT controls following 120 min-and 50 min-ischemia/reperfusion,respectively.Conclusions:The role of NF-κB in intestinal ischemia-reperfusion injury remains controversial.The present study found that NF-κB exerts pathogenic and protective roles as well as pro-inflammatory and anti-inflammatory functions in the pathophysiological process of intestinal I/R injury.These dual roles for NF-κB depend on the severity of intestinal I/R injury,with a pro-inflammatory and injurious role in lethal ischemia but an anti-inflammatory and protective role in low-lethal ischemia.These findings implicate an important function of NF-κB in maintaining intestinal homeostasis and might thus allow us to cautiously consider NF-κB signaling as a therapeutic target against intestinal ischemia-reperfusion injury.