Objective:To observe the inhibitory effect of dexmedetomidine on autophagic apoptosis induced by intestinal ischemia-reperfusion through HMGB1/TLR4/NF-κB. Methods: Forty healthy male SD rats were randomly divided into control group, ischemia-reperfusion group (I/R group), low-dose dexmedetomidine+ischemia-reperfusion group (D1 group), medium-dose dexmedetomidine+ischemia-reperfusion group (D2 group) and high-dose dexmedetomidine+ischemia-reperfusion group (D3 group), 8 rats in each group. Rats in all 5 groups were given intraperitoneal injection of 1% pentobarbital sodium for 50 mg/kg. After satisfactory anesthesia, the superior mesenteric artery was exposed by blunt separation through a median abdominal incision, and the superior mesenteric artery was clamped for 60 min and then reperfused for 60 min to establish intestinal ischemia-reperfusion model. The control group only underwent laparotomy for 120 min, without clamping the superior mesenteric artery. Group D1, D2 and D3 were given dexmetomidine 1 μg/kg,5 μg/kg and 10 μg/kg via caudal vein 10 min before clamping, respectively, while the control group and I/R group were given the same amount of normal saline. The pathological changes of intestinal tissue were observed by HE staining, and the levels of serum inflammatory factors TNF-α, IL-1 and HMGB1 were detected by ELISA. The protein expression levels of Beclin-1, HMGB1, TLR4 and NF-κB in intestinal tissue were detected by Western blotting, and the apoptosis of intestinal tissue was detected by TUNEL. Results: Compared with the control group, there was neutrophils infiltration in the intestinal tissue of I/R group, but only a few inflammatory cells infiltrated in group D1, D2 and D3. Compared with the control group, the levels of serum inflammatory cytokines TNF-α, IL-1 and HMGBI ingroups I/R,D1,D2 and D3 were higher, and the levels of TNF-α, IL-1 and HMGB1 in group D1, D2 and D3 were lower than those in group I/R. Compared with the control group, the expression of Beclin-1, HMGB1, TLR4 and NF-κB protein in intestinal tissue of group I/R,D1, D2 and D3 increased, while the expression of Beclin-1, HMGB1, TLR4 and NF-κB protein decreased in group D1, D2 and D3 as compared with that of group I/R. Compared with the control group, the number of TUNEL positive cells in group I/R was significantly increased, and the number of TUNEL positive cells in group D1, D2 and D3 were significantly lower than that in group I/R (P<0.05). Conclusion: Intestinal ischemia-reperfusion injury activates autophagic apoptosis. Dexmetomidine plays a protective role in intestinal ischemia-reperfusion injured by inhibiting autophagic apoptosis induced by intestinal ischemia-reperfusion through HMGB1/TLR4/NF-κB.
 MURPHY K P,TWOMEY M,McLAUGHLIN P D,et al.Imaging of ischemia,obstruction and infection in the abdomen[J].Radiol Clin North Am,2015,53(4):847-869.
 WANG C,CHEN K,XIA Y,et al.N-acetylcysteine attenuates ischemia-reperfusion induced apoptosis and autophagy in mouse liver via regulation of the ROS/JNK/Bcl-2 pathway[J].PLoS One,2014,9(9):e108855.
 CAI Y,XU H,YAN J,et al.Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury[J].Mol Med Rep,2014,9(5):1542-1550.
 BELL M T,PUSKAS F,BENNETT D T,et al.Dexmedetomidine,an α-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion[J].J Thorac Cardiovasc Surq,2014,147(1):500-506.
 MITSUOKA H,SCHMID-SCHŌNBEIN G W.Mechanisms for blockade of in vivo activator production in the ischemic intestine and multi-organ failure[J].Shock,2000,14(5):522-527.
 STALLION A,KOU T D,LATIFI S Q,et al.Ischemia/reperfusion:a clinically relevant model of intestinal injury yielding systemic inflammation[J].J Pediatr Surg,2005,40(3):470-477.
 DING H S,YANG J,GONG F L,et al.High mobility group[corrected]box 1 mediates neutrophil recruitment in myocardial ischemia-reperfusion injury through toll like receptor 4-related pathway[J].Gene,2012,509(1):149-153.
 ZOU L,ATTUWAYBI B,KONE B C.Effects of NF-kappa B inhibition on mesenteric ischemia-reperfusion injury[J].Am J Physiol Gasmintest Liver Physiol,2003,284(4):G713-G721.
 TANG D,LOZE M T,ZEH H J,et al.The redox protein HMGB1 regulates cell death and survival in cancer treatment[J].Autophagy,2010,6(8):1181-1183.
 SUN Y, LIU J H, JIN L, et al.Beclin-1 influences cisplatin-induced apoptosis in cervical cancer CaSki cells by mitochondrial dependent pathway[J].Int J Gynecol Cancer,2012,22(7):1118-1124.
 KIM S Y, SONG X, ZHANG L, et al.Role of Bcl-xL/Beclin-1 in interplay between apoptosis and autophagy in oxaliplatin and bortezomib-induced cell death[J].Biochem Pharmacol,2014,88(2):178-188.
 SHOU-SHI W,TING-TING S,JI-SHUN N,et al.Preclinical efficacy of dexmedetomidine on spinal cord injury provoked oxidative renal damage[J].Ren Fail,2015,37(7):1190-1197.
 ZHANG J,WANG Z,WANG Y,et al.The effect of dexmedetomidine on inflammatory response of septic rats[J].BMC Anesthesiol,2015,15:68.
 WEERINK M A S,STRUYS M M R F,HANNIVOORT L N,et al.Clinical pharmacokinetics and pharmacodynamic of dexmedetomidine[J].Clin Pharmacokinet,2017,56(8):893-913.
 ABRAHAM E,LATERRE P F,GARG R,et al.Drotrecogin alfa(activated)for adults with severe sepsis and a low risk of death[J].N Engl J Med,2005,353(13):1332-1341.
 TAYLOR R W,MANGANARO L,O'BRIEN J,et al.Impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patients[J].Crit Care Med,2002,30(10):2249-2254.
 BELL M T,PUSKAS F,BENNETT D T,et al.Dexmedetomidine, an α-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion[J].J Thorac Cardiovasc Surg,2014,147(1):500-506.
 ZHANG X Y, LIU Z M, WEN S H, et al.Dexmedetomidine administration before,but not after,ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats[J].Anesthesiology, 2012,116(5):1035-1046.
 SEGAL I S,VICKERY R G,WALTON J K,et al.Dexmedetomidine diminishes halothane anesthetic requirements in rats through a postsynaptic alpha-2 adrenergic receptor[J].Anesthesiology,198869(6):818-823.