TNF-α and plasma D(-)-lactate levels in rats after intestinal ischemia and reperfusion

Objective To study the potential role of tumor necrosis factor-α (TNF-α) induction in the development of mucosal barrier dysfunction in rats caused by acute intestinal ischemia-reperfusion injury, and to examine whether pretreatment with monoclonal antibody against TNF-α (TNF-α MoAb) would affect the release of D(-)-lactate after local gut ischemia followed by reperfusion. Methods Anesthetized Sprague-Dawley rats underwent superior mesenteric artery occlusion for 75 min followed by reperfusion for 6 hr. The rats were treated intravenously with either TNF-α MoAb (20 mg/kg) or albumin (20 mg/kg) 30 min prior to the onset of ischemia. Plasma D(-)-lactate levels were measured in both the portal and systemic blood by an enzymatic spectrophotometric assay. Intestinal TNF-αmRNA expression as well as protein levels were also measured at various intervals. In addition, a postmortem examination was performed together with a macropathological evaluation based on a four-grade scoring system.Results Intestinal ischemia resulted in a significant elevation in D(-)-lactate levels in the portal vein blood in both the control and treatment groups ( P ＜0.05). However, animals pretreated with TNF-α MoAb at 6 hr after reperfusion showed significant attenuation of an increase in both portal and systemic D(-)-lactate levels when compared with those only receiving albumin (P ＜ 0.05). In the control animals, a remarkable rise in intestinal TNF-α level was measured at 0.5 hr after clamp release ( P ＜ 0.01); however, prophylactic treatment with TNF-α MoAb completely annulled the increase of local TNF-α levels seen in the control animals. Similarly, after anti-TNF-α MoAb administration, intestinal TNF-α mRNA expression was markedly inhibited, which showed significant differences when compared with the control group at 0.5 hr, 2 hr and 6 hr after the release of occlusion ( P ＜ 0.05-0.01 ). In addition, the pathological examination showed marked intestinal lesions that formed during ischemia, which were much worse upon reperfusion,particularly at the 6 hr time point. These acute injuries were obviously attenuated in animals receiving TNF-α MoAb.Conclusions It appeared that acute intestinal ischemia was associated with failure of the mucosal barrier, resulting in increased plasma D(-)-lactate levels in both portal and systemic blood. These results suggest that TNF-α appears to be involved in the development of local damage associated with intestinal ischemic injury. Moreover, prophylactic treatment with TNF-α MoAb exerts preventive effects on ischemia/ reperfusion-induced circulating D (-)-lactate elevation and gut injury. ( J Geriatr Cardiol 2004;1(2):119-124. )

Objective To study the potential role of tumor necrosis factor-or(TNF-α)induction in the development of mucosal barrier dysfunction in rats caused by acute intestinal ischemia-reperfusion injury,and to examine whether pretreatment with monoclonal antibody against TNF-α(TNF-αMoAb)would affect the release of D(-)-lactate after local gut ischemia followed by reperfusion.Methods Anesthetized Sprague-Dawley rats underwent superior mesenteric artery occlusion for 75 min followed by reperfusion for 6 hr.The rats were treated intravenonsly with either TNF-α MoAb(20 mg/kg)or albumin(20 mg/kg)30 min prior to the onset of ischemia.Plasma D(-)-lactate levels were measured in both the portal and systemic blood by an enzymatic spectrophotometrie assay.Intestinal TNF-α mRNA expression as well as protein levels were also measured at various intervals.In addition,a postmortem examination was performed together with a macropatholngical evaluation based on a four-grade scoring system. Results Intestinal ischemia resulted in a significant elevation in D(-)-lactate levels in the portal vein blood in both the control and treatment groups(P<0.05).However,animals pretreated with TNF-α MoAb at 6 hr after reperfusion showed significant attenuation of an increase in both portal and systemic D(-)-lactate levels when compared with those only receiving albumin(P<0.05).In the control animals,a remarkable rise in intestinal TNF-α level was measured at 0.5 hr after clamp release(P<0.01);however,prophylactic treatment with TNF-α MoAb completely annulled the increase of local TNF-α levels seen in the control animals.Similarly,after anti-TNF-α MoAb administration,intestinal TNF-α mRNA expression was markedly inhibited,which showed significant differences when compared with the control group at 0.5 hr,2 hr and 6 hr after the release of occlusion(P<0.05-0.01).In addition,the pathological examination showed marked intestinal lesions that formed during ischemia,which were much worse upon reperfusion, particularly at the 6 hr time point.These acute injuries were obviously attenuated in animals receiving TNF-α MoAb. Conclusions It appeared that acute intestinal ischemia was associated with failure of the mucosal barrier,resulting in increased plasma D(-)-lactate levels in both portal and systemic blood.These results suggest that TNF-α appears to be involved in the development of local damage associated with intestinal ischemic injury.Moreover,prophylactic treatment with TNF-α MoAb exerts preventive effects on ischemia/reperfusion-induced circulating D(-)-lactate elevation and gut injury.(J Geriatr Cardiol 2004;1(2):119-124.)