Dual Role Of NF-?B 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-?B plays a critical role in the regulation of inflammatory and innate immune responses.The role of NF-?B 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-?B 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-?B1?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-?B in intestinal mucosa.Results:NF-?B was rapidly activated following intestinal I/R in intestinal mucosa and the activated NF-?B complexes predominantly involve p50/p65 but also p50/p50.The majority of?B DNA-binding activity in intestinal mucosa was abrogated from p50^-/-mice during intestinal I/R.Gross and histological examination showed that NF-?B 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-?B?-/-?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-?B?-/-?mice compared with WT controls.The mucosal MPO activities were largely decreased and drastically increased in NF-?B?-/-?mice compared with WT controls following 120 min-and 50 min-ischemia/reperfusion,respectively.Conclusions:The role of NF-?B in intestinal ischemia-reperfusion injury remains controversial.The present study found that NF-?B 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-?B 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-?B in maintaining intestinal homeostasis and might thus allow us to cautiously consider NF-?B signaling as a therapeutic target against intestinal ischemia-reperfusion injury.