Cardiopulmonary bypass can result in damage to the intestines, leading to the occurrence of systemic inflammatory response syndrome. Dexmedetomidine is reported to confer anti-inflammatory properties. Here, the purpose of this study is to investigate the effect of dexmedetomidine on the intestinal mucosa barrier damage in a rat model of cardiopulmonary bypass. It was observed that cardiopulmonary bypass greatly decreased the levels of hemodynamic parameters than SHAM group, whereas dexmedetomidine pretreatment in a cardiopulmonary bypass model rat prevented this reduction. Also, it showed that compared with control animals, cardiopulmonary bypass caused obvious mucosal damage, which was attenuated in dexmedetomidine + cardiopulmonary bypass group. The above findings were in line with that of dexmedetomidine pretreatment, which increased the expression of tight junction proteins, but it decreased the levels of DAO, D-LA, FABP2, and endotoxin. Moreover, the results demonstrated that due to pre-administration of dexmedetomidine, the level of pro-inflammatory factors was decreased, while the level of anti-inflammatory cytokine was increased. Also, it showed that dexmedetomidine suppressed TLR4/JAK2/STAT3 pathway that was activated by cardiopulmonary bypass. Together, these results revealed that dexmedetomidine pretreatment relieves intestinal microcirculation, attenuates intestinal damage, and inhibits the inflammatory response of cardiopulmonary bypass model rats, demonstrating that in CPB-induced damage of intestinal mucosal barrier function, dexmedetomidine pretreatment plays a protective role by inactivating TLR4/JAK2/STAT3-mediated inflammatory pathway.
RiddingtonDWVenkateshBBoivinCMBonserRSElliottTSMarshallTMountfordPJBionJF.Intestinal permeability, gastric intramucosal pH, and systemic endotoxemia in patients undergoing cardiopulmonary bypass. Jama1996;
275:1007–12
2.
AydinNBGercekogluHAksuBOzkulVSenerTKiygilITurkogluTCimenSBabacanFDemirtasM.Endotoxemia in coronary artery bypass surgery: a comparison of the off-pump technique and conventional cardiopulmonary bypass. J Thorac Cardiovasc Surg2003;
125:843–8
3.
HirataY.Cardiopulmonary bypass for pediatric cardiac surgery. Gen Thorac Cardiovasc Surg2018;
66:65–70
4.
ChawlaBKTeitelbaumDH.Profound systemic inflammatory response syndrome following non-emergent intestinal surgery in children. J Pediatr Surg2013;
48:1936–40
5.
OsukaAKusukiHMatsuuraHShimizuKOguraHUeyamaM.Acute intestinal damage following severe burn correlates with the development of multiple organ dysfunction syndrome: a prospective cohort study. Burns2017;
43:824–9
6.
GeisslerHJFischerUMGrunertSKuhn-RégnierFHoelscherASchwingerRHMehlhornUHekmatK.Incidence and outcome of gastrointestinal complications after cardiopulmonary bypass. Interact Cardiovasc Thorac Surg2006;
5:239–2342
7.
HashemzadehKHashemzadehS.Predictors and outcome of gastrointestinal complications after cardiac surgery. Minerva Chir2012;
67:327–35
8.
MojcikCFLevyJH.Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg2001;
71:745–54
9.
ThorénANygrenAHoultzERickstenSE.Cardiopulmonary bypass in humans–jejunal mucosal perfusion increases in parallel with well-maintained microvascular hematocrit. Acta Anaesthesiol Scand2005;
49:502–9
10.
SackFUReidenbachBSchledtADollnerRTaylorSGebhardMMHaglS.Dopexamine attenuates microvascular perfusion injury of the small bowel in pigs induced by extracorporeal circulation. Br J Anaesth2002;
88:841–7
11.
GyiresKZádoriZSShujaaNMinoricsRFalkayGMátyusP.Analysis of the role of Central and peripheral alpha2-adrenoceptor subtypes in gastric mucosal defense in the rat. Neurochem Int2007;
51:289–96
12.
MüllnerKRónaiAZFülöpKFürstSGyiresK.Involvement of central K(ATP) channels in the gastric antisecretory action of alpha2-adrenoceptor agonists and beta-endorphin in rats. Eur J Pharmacol2002;
435:225–9
13.
GyiresKMüllnerKRónaiAZ.Functional evidence that gastroprotection can be induced by activation of central alpha(2B)-adrenoceptor subtypes in the rat. Eur J Pharmacol2000;
396:131–5
14.
AsaiTMaplesonWWPowerI.Differential effects of clonidine and dexmedetomidine on gastric emptying and gastrointestinal transit in the rat. Br J Anaesth1997;
78:301–7
15.
UmezawaTGuoSJiaoYHisamitsuT.Effect of clonidine on colonic motility in rats. Auton Neurosci2003;
107:32–6
16.
MantzJJosserandJHamadaS.Dexmedetomidine: new insights. Eur J Anaesthesiol2011;
28:3–6
17.
XianbaoLHongZXuZChunfangZDunjinC.Dexmedetomidine reduced cytokine release during postpartum bleeding-induced multiple organ dysfunction syndrome in rats. Mediators Inflamm2013;
2013:627831
18.
MemişDHekimoğluSVatanIYandimTYükselMSütN.Effects of midazolam and dexmedetomidine on inflammatory responses and gastric intramucosal pH to sepsis, in critically ill patients. Br J Anaesth2007;
98:550–2
19.
ShiQQWangHFangH.Dose-response and mechanism of protective functions of selective alpha-2 agonist dexmedetomidine on acute lung injury in rats. Saudi Med J2012;
33:375–81
20.
LaiYCTsaiPSHuangCJ.Effects of dexmedetomidine on regulating endotoxin-induced up-regulation of inflammatory molecules in murine macrophages. J Surg Res2009;
154:212–9
21.
ShaJZhangHZhaoYFengXHuXWangCSongMFanH.Dexmedetomidine attenuates lipopolysaccharide-induced liver oxidative stress and cell apoptosis in rats by increasing GSK-3β/MKP-1/Nrf2 pathway activity via the α2 adrenergic receptor. Toxicol Appl Pharmacol2019;
364:144–52
22.
ZhangXWangJQianWZhaoJSunLQianYXiaoH.Dexmedetomidine inhibits tumor necrosis factor-alpha and interleukin 6 in lipopolysaccharide-stimulated astrocytes by suppression of c-Jun N-terminal kinases. Inflammation2014;
37:942–9
23.
QiaoHSandersRDMaDWuXMazeM.Sedation improves early outcome in severely septic Sprague Dawley rats. Crit Care2009;
13:R136
24.
WuYLiuYHuangHZhuYZhangYLuFZhouCHuangLLiXZhouC.Dexmedetomidine inhibits inflammatory reaction in lung tissues of septic rats by suppressing TLR4/NF-κB pathway. Mediators Inflamm2013;
2013:562154
25.
HodgeDRHurtEMFarrarWL.The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer2005;
41:2502–12
26.
SchindlerCDarnellJEJr.Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem1995;
64:621–51
27.
ChenYZhangXZhangBHeGZhouLXieY.Dexmedetomidine reduces the neuronal apoptosis related to cardiopulmonary bypass by inhibiting activation of the JAK2-STAT3 pathway. Drug Des Devel Ther2017;
11:2787–99
28.
ChenKSunWJiangYChenBZhaoYSunJGongHQiR.Ginkgolide B suppresses TLR4-mediated inflammatory response by inhibiting the phosphorylation of JAK2/STAT3 and p38 MAPK in high glucose-treated HUVECs. Oxid Med Cell Longev2017;
2017:9371602
29.
PanSChenYZhangXXieY.The JAK2/STAT3 pathway is involved in dexmedetomidine-induced myocardial protection in rats undergoing cardiopulmonary bypass. Ann Transl Med2020;
8:483
30.
GourlayTBallauxPKDraperERTaylorKM.Early experience with a new technique and technology designed for the study of pulsatile cardiopulmonary bypass in the rat. Perfusion2002;
17:191–8
31.
ZhangXSunYSongDDiaoY.κ-opioid receptor agonists may alleviate intestinal damage in cardiopulmonary bypass rats by inhibiting the NF-κB/HIF-1α pathway. Exp Ther Med2020;
20:325–34
32.
KalakechHTamareilleSPonsSGodin-RibuotDCarmelietPFurberAMartinVBerdeauxAGhalehBPrunierF.Role of hypoxia inducible factor-1α in remote limb ischemic preconditioning. J Mol Cell Cardiol2013;
65:98–104
33.
LongQFanCKaiWLuoQXinWWangPWangAWangZHanRFeiZQiuBLiuW.Hypoxia inducible factor-1α expression is associated with hippocampal apoptosis during epileptogenesis. Brain Res2014;
1590:20–30
34.
FasanoA.Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol2012;
10:1096–100
35.
SunYJCaoHJSongDDDiaoYGZhouJZhangTZ.Probiotics can alleviate cardiopulmonary bypass-induced intestinal mucosa damage in rats. Dig Dis Sci2013;
58:1528–36
36.
HeCDengJHuXZhouSWuJXiaoDDarkoKOHuangYTaoTPengMWangZYangX.Vitamin a inhibits the action of LPS on the intestinal epithelial barrier function and tight junction proteins. Food Funct2019;
10:1235–42
37.
SunTLiangHXueMLiuYGongAJiangYQinYYangJMengD.Protective effect and mechanism of fucoidan on intestinal mucosal barrier function in NOD mice. Food Agr Immunol2020;
31:939–53
38.
SunYJChenWMZhangTZCaoHJZhouJ.Effects of cardiopulmonary bypass on tight junction protein expressions in intestinal mucosa of rats. Wjg2008;
14:5868–75
39.
LiuZSunXTangJTangYTongHWenQLiuYSuL.Intestinal inflammation and tissue injury in response to heat stress and cooling treatment in mice. Mol Med Rep2011;
4:437–43
40.
ChenYMiaoLYaoYWuWWuXGongCQiuLChenJ.Dexmedetomidine ameliorate CLP-induced rat intestinal injury via inhibition of inflammation. Mediators Inflamm2015;
2015:918361
41.
ZhouZXuMJGaoB.Hepatocytes: a key cell type for innate immunity. Cell Mol Immunol2016;
13:301–15
42.
MooreKWde Waal MalefytRCoffmanRLO'GarraA.Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol2001;
19:683–765
43.
JoHAKimJYYangSHHanSSJooKWKimYSKimDK.The role of local IL6/JAK2/STAT3 signaling in high glucose-induced podocyte hypertrophy. Kidney Res Clin Pract2016;
35:212–8
44.
AroorARMcKarnsSDemarcoVGJiaGSowersJR.Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism2013;
62:1543–52
45.
LiMSongLGaoXChangWQinX.Toll-like receptor 4 on islet β cells senses expression changes in high-mobility group box 1 and contributes to the initiation of type 1 diabetes. Exp Mol Med2012;
44:260–7
SongDLiuXDiaoYSunYGaoGZhangTChenKPeiL.Hydrogen‑rich solution against myocardial injury and aquaporin expression via the PI3K/akt signaling pathway during cardiopulmonary bypass in rats. Mol Med Rep2018;
18:1925–38
48.
TsunookaNHamadaYImagawaHNakamuraYShiozakiTSuzukiHKikkawaHMiyauchiKWatanabeYKawachiK.Ischemia of the intestinal mucosa during cardiopulmonary bypass. J Artif Organs2003;
6:149–51
49.
DongGHWangCTLiYXuBQianJJWuHWJingH.Cardiopulmonary bypass induced microcirculatory injury of the small bowel in rats. World J Gastroenterol2009;
15:3166–72
50.
DeitchEA.The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. Arch Surg1990;
125:403–4
51.
OhriSKBjarnasonIPathiVSomasundaramSBowlesCTKeoghBEKhaghaniAMenziesIYacoubMHTaylorKM.Cardiopulmonary bypass impairs small intestinal transport and increases gut permeability. Ann Thorac Surg1993;
55:1080–6
52.
PaparellaDYauTMYoungE.Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur J Cardiothorac Surg2002;
21:232–44
53.
SunYJCaoHJ, JQDiaoYGZhangTZ.Effects of penehyclidine hydrochloride on rat intestinal barrier function during cardiopulmonary bypass. Wjg2011;
17:2137–42
54.
HsuYWCortinezLIRobertsonKMKeiferJCSum-PingSTMorettiEWYoungCCWrightDRMacleodDBSommaJ.Dexmedetomidine pharmacodynamics: part I: crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology2004;
101:1066–76
55.
TaniguchiTKidaniYKanakuraHTakemotoYYamamotoK.Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats. Crit Care Med2004;
32:1322–6
56.
UekiMKawasakiTHabeKHamadaKKawasakiCSataT.The effects of dexmedetomidine on inflammatory mediators after cardiopulmonary bypass. Anaesthesia2014;
69:693–700
57.
GaoZLiZDengRLiuQXiaoQHanJPuCZhangY.Dexmedetomidine improves postoperative neurocognitive disorder after cardiopulmonary bypass in rats. Neurol Res2021;
43:164–72
58.
WangLWangSXingZLiFTengJJiaT.Application of dexmedetomidine in cardiopulmonary bypass prefilling. Dose Response2020;
18:1559325820939764
59.
GezeSCekicBImamoğluMYörükMFYuluğEAlverAMenteseAErtürkETusatM.Use of dexmedetomidine to prevent pulmonary injury after pneumoperitoneum in ventilated rats. Surg Laparosc Endosc Percutan Tech2012;
22:447–53
60.
CaiYXuHYanJZhangLLuY.Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. Mol Med Rep2014;
9:1542–50
61.
LawrenceCJPrinzenFWde LangeS.The effect of dexmedetomidine on nutrient organ blood flow. Anesth Analg1996;
83:1160–5
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