| The small intestine is the most sensitive organ to ischemia reperfusion(I/R)injury.In the case of hemorrhagic shock,trauma ileus and so on,the ischemic injury of the small intestine is unavoidable,and lifting or alleviate ischemia injury may cause the reperfusion injury of the small intestine.The pathophysiological mechanisms of intestine ischemia reperfusion injury are very complex,involving injury of oxygen free radical,adhesive infiltration of leukocyte,the release of inflammatory mediators,and disorder of energy metabolism etc.Among them,the excessive production of reactive oxygen species,inflammatory medium and infiltrating activation of neutrophils is a key link in process of intestinal ischemia reperfusion injury [1].Interleukin-1 receptor antagonist(IL-1Ra)is a natural anti-inflammatory factor and displays an important action in immune regulation and the inhibition of inflammation [2].IL-1Ra can compete with Interleukin-1(IL – 1)in combining with IL-1 receptors on the cell membrane,thus antagonism IL-1 signal transmission and blocking its biological function.Previous studies demonstrated that IL-1Ra also had a certain capability to clear free radical and to intensify the endogenous antioxidative system,thus possessing a certain therapeutic effects on the I/R injuryinduced oxidative stress of brain,ovary and other organs [3].However,it is unclear whether IL-1Ra has a certain preventive and therapeutic effect on intestine ischemia reperfusion injury or not.Our study is to explore the effects and possible mechanism of interleukin-1 receptor antagonist on intestinal ischemia-reperfusion induced injury by clipping superior mesenteric artery of rat.Thirty five male SD rats were randomly divided into sham operation group(S),model group(I/R),different dosage drug group(C1,C2,C3).Rat intestinal I/R model was established via clamping the superior mesenteric artery(SMA).After 1 h of ischemia,release the arterial clamps for 1 h of reperfusion.10 mg·kg-1,20 mg·kg-1,30 mg·kg-1 of IL-Ra was injected via caudal vein 15 min before reperfusion.After the completion of the experiment,we detecting the leaves of intestinal tissue inflammation,oxidative stress and cell apoptosis,and further testing the changes of MAPKs and Nrf2 signaling pathways in intestinal tissues.The results showed that,the I/R group compared with the S group had more serious intestinal mucosa damage with more TUNEL positive cells and higher content of MPO,MDA,IL-1?,IL-6 and TNF-?,while reduced activity of SOD in intestinal tissues.In terms of apoptosis-related proteins,the expression of casepase-3 and Bax were increased while expression level of Bcl-xl was decreased remarkably in model group.However,in IL-1RA group,the IL-1RA treatment ameliorated mucosa damage on intestinal morphometry,which was accompanied by Inhibiting inflammatory effect and oxidative stress effect on intestinal mucosa and also decreased expression of apoptosis-related proteins in comparison to the model group.Mechanically,it was found through Western Blotting that in comparison to the control group,the phosphorylation levels of JNK,p38 MAPK and ERK were higher in intestine tissues of model group.In addition,the model group showed a little increase in phosphorylation level of Nrf2 and also the expression level of HO-1.Conversely,in the IL-1RA group,level of p-JNK,p-p38 MAPK and p-ERK were significantly decreased whereas the phosphorylation level of Nrf2 and expression of HO-1 were notably higher than those in model group.Thus we can conclude:1.IL-1Ra showed obvious protective effect on intestinal ischemia reperfusion induced injury by relieving inflammatory response,oxidative stress,and intestinal cells apoptosis,and it is expected to be used in treatment of intestinal ischemia reperfusion injury.2.IL-1Ra can effectively inhibit the MAPKs signaling pathways and further activation of Nrf2/HO-1 signaling pathways,prompting the protective effect of IL- 1Ra on intestinal ischemia reperfusion injury may be closely related to the MAPKs and Nrf2/HO-1 signaling pathways... |
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