Vol 60, No 4 (2022)
Original paper
Published online: 2022-12-09
Dexmedetomidine alleviates intestinal barrier dysfunction and inflammatory response in mice via suppressing TLR4/MyD88/NF-κB signaling in an experimental model of ulcerative colitis
Abstract
Introduction. Ulcerative colitis (UC) is a nonspecific intestinal inflammatory disease. Dexmedetomidine (DEX) is a selective alpha 2-adrenergic receptor agonist commonly used for analgesia and sedation in intensive care units. Herein, the role and mechanism of DEX in dextran sulfate sodium (DSS)-induced colitis was explored.
Materials and methods. A murine model of DSS-induced colitis was established by adding 3.5% (w/v) DSS in drinking water to C57BL/6J female mice. The severity of colitis was measured by the disease activity index (DAI) score, colon length and body weight of mice. The serum concentration and mRNA levels of inflammatory cytokines in colon tissues were assessed by ELISA and RT-qPCR, respectively. Protein levels of apoptotic markers, tight junction proteins and genes involved in the TLR4/MyD88/NF-κB signaling were quantified utilizing Western blotting. The pathological changes of colon tissues were evaluated by hematoxylin-eosin (HE) staining and histological score. Intestinal permeability in vivo was assessed by fluorescein isothiocyanate (FITC)–dextran (FITC-D) administration. TUNEL assay was used to determine cell apoptosis in the intestinal epithelium.
Results. DSS administration resulted in weight loss, shortening of the colon, increased DAI score, histological abnormalities, and increased serum FITC-D levels in mice, all of which were reversed by DEX injection. Moreover, DEX attenuated DSS-triggered inflammatory response, intestinal barrier injury and intestinal epithelial cell apoptosis. Mechanically, DEX inactivated the TLR4/MyD88/NF-κB signaling in the colon tissues.
Conclusions. DEX exerts beneficial effects against the intestinal barrier dysfunction, inflammatory response, and apoptosis of intestinal epithelial cells via inactivation of the TLR4/MyD88/NF-κB signaling in mice with DSS-induced colitis.
Keywords: mouseDSSexperimental colitisdexmedetomidinecytokinesTLR4/MyD88/NF-κBintestinal barrier
References
- Liu D, Saikam V, Skrada KA, et al. Inflammatory bowel disease biomarkers. Med Res Rev. 2022; 42(5): 1856–1887.
- Ramos GP, Dimopoulos C, McDonald NM, et al. The impact of vedolizumab on pre-existing extraintestinal manifestations of inflammatory bowel disease: a multicenter study. Inflamm Bowel Dis. 2021; 27(8): 1270–1276.
- Eisenstein M. Ulcerative colitis: towards remission. Nature. 2018; 563(7730): S33.
- Kangwan N, Pintha K, Khanaree C, et al. Anti-inflammatory effect of seed oil rich in omega-3 fatty acid on dextran sodium sulfate-induced colitis in mice. Res Pharm Sci. 2021; 16(5): 464–473.
- Pang B, Jin H, Liao N, et al. Vitamin A supplementation ameliorates ulcerative colitis in gut microbiota-dependent manner. Food Res Int. 2021; 148: 110568.
- Yamamoto-Furusho JK, Gutiérrez-Grobe Y, López-Gómez JG, et al. Grupo del Consenso Mexicano de Colitis Ulcerosa Crónica Idiopática. The Mexican consensus on the diagnosis and treatment of ulcerative colitis. Rev Gastroenterol Mex (Engl Ed). 2018; 83(2): 144–167.
- Ebrahim HA, Elsherbini DM. Renovation of intestinal barrier by polydatin in experimentally induced ulcerative colitis: comparative ultrastructural study with l-carnosine. Cells Tissues Organs. 2021; 210(4): 275–292.
- Gou HZ, Zhang YL, Ren LF, et al. How do intestinal probiotics restore the intestinal barrier? Front Microbiol. 2022; 13: 929346.
- Dillard JP. Hold it right there! Gonococci preserve epithelium integrity during intimate adherence. Cell Host Microbe. 2020; 27(5): 685–686.
- Wang Z, Cao Y, Zhang K, et al. Gold nanoparticles alleviates the lipopolysaccharide-induced intestinal epithelial barrier dysfunction. Bioengineered. 2021; 12(1): 6472–6483.
- Panwar S, Sharma S, Tripathi P. Role of barrier integrity and dysfunctions in maintaining the healthy gut and their health outcomes. Front Physiol. 2021; 12: 715611.
- Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015; 75(10): 1119–1130.
- Schnabel A, Meyer-Frießem CH, Reichl SU, et al. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain. 2013; 154(7): 1140–1149.
- Wang X, Liu Q. Dexmedetomidine relieved neuropathic pain and inflammation response induced by CCI through HMGB1/TLR4/NF-κB signal pathway. Biol Pharm Bull. 2021 [Epub ahead of print].
- Xie Y, Jiang W, Cao J, et al. Dexmedetomidine attenuates acute kidney injury in children undergoing congenital heart surgery with cardiopulmonary bypass by inhibiting the TLR3/NF-κB signaling pathway. Am J Transl Res. 2021; 13(4): 2763–2773.
- Tasdogan M, Memis D, Sut N, et al. Results of a pilot study on the effects of propofol and dexmedetomidine on inflammatory responses and intraabdominal pressure in severe sepsis. J Clin Anesth. 2009; 21(6): 394–400.
- Qin C, Jiang Yi, Chen X, et al. Dexmedetomidine protects against burn-induced intestinal barrier injury via the MLCK/p-MLC signalling pathway. Burns. 2021; 47(7): 1576–1585.
- Yang J, Wu Y, Xu Y, et al. Dexmedetomidine resists intestinal ischemia-reperfusion injury by inhibiting TLR4/MyD88/NF-κB signaling. J Surg Res. 2021; 260: 350–358.
- Xu SQ, Li YH, Wang SB, et al. Effects of intravenous lidocaine, dexmedetomidine and their combination on postoperative pain and bowel function recovery after abdominal hysterectomy. Minerva Anestesiol. 2017; 83(7): 685–694.
- Liu XM, Chen QH, Hu Q, et al. Dexmedetomidine protects intestinal ischemia-reperfusion injury via inhibiting p38 MAPK cascades. Exp Mol Pathol. 2020; 115: 104444.
- Erdogan Kayhan G, Gul M, Kayhan B, et al. Dexmedetomidine ameliorates TNBS-induced colitis by inducing immunomodulator effect. J Surg Res. 2013; 183(2): 733–741.
- Qu Y, Li X, Xu F, et al. Kaempferol alleviates murine experimental colitis by restoring gut microbiota and inhibiting the LPS-TLR4-NF-κB axis. Front Immunol. 2021; 12: 679897.
- Hu J, Huang H, Che Y, et al. Qingchang huashi formula attenuates DSS-induced colitis in mice by restoring gut microbiota-metabolism homeostasis and goblet cell function. J Ethnopharmacol. 2021; 266: 113394.
- Wu M, Li P, An Y, et al. Phloretin ameliorates dextran sulfate sodium-induced ulcerative colitis in mice by regulating the gut microbiota. Pharmacol Res. 2019; 150: 104489.
- Cao Y, Chen Q, Wang Z, et al. PLK1 protects against sepsis-induced intestinal barrier dysfunction. Sci Rep. 2018; 8(1): 1055.
- Kyrylkova K, Kyryachenko S, Leid M, et al. Detection of apoptosis by TUNEL assay. Methods Mol Biol. 2012; 887: 41–47.
- Liang B, Zhong Y, Huang Y, et al. Underestimated health risks: polystyrene micro- and nanoplastics jointly induce intestinal barrier dysfunction by ROS-mediated epithelial cell apoptosis. Part Fibre Toxicol. 2021; 18(1): 20.
- Wang Y, Lin J, Cheng Z, et al. Bacillus coagulans TL3 inhibits LPS-induced caecum damage in rat by regulating the TLR4/MyD88/NF- κB and Nrf2 signal pathways and modulating intestinal microflora. Oxid Med Cell Longev. 2022; 2022: 5463290.
- Wang W, Xia T, Yu X. Wogonin suppresses inflammatory response and maintains intestinal barrier function via TLR4-MyD88-TAK1-mediated NF-κB pathway in vitro. Inflamm Res. 2015; 64(6): 423–431.
- Kaenkumchorn T, Wahbeh G. Ulcerative colitis: making the diagnosis. Gastroenterol Clin North Am. 2020; 49(4): 655–669.
- Yan YX, Shao MJ, Qi Q, et al. Artemisinin analogue SM934 ameliorates DSS-induced mouse ulcerative colitis via suppressing neutrophils and macrophages. Acta Pharmacol Sin. 2018; 39(10): 1633–1644.
- Eichele DD, Kharbanda KK. Dextran sodium sulfate colitis murine model: An indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis. World J Gastroenterol. 2017; 23(33): 6016–6029.
- Munyaka PM, Rabbi MF, Khafipour E, et al. Acute dextran sulfate sodium (DSS)-induced colitis promotes gut microbial dysbiosis in mice. J Basic Microbiol. 2016; 56(9): 986–998.
- Woting A, Blaut M. Small intestinal permeability and gut-transit time determined with low and high molecular weight fluorescein isothiocyanate-dextrans in C3H mice. Nutrients. 2018; 10(6): 685.
- Li H, Xuan Ji, Zhang W, et al. Long non-coding RNA SNHG5 regulates ulcerative colitis via microRNA-375 / Janus kinase-2 axis. Bioengineered. 2021; 12(1): 4150–4158.
- Dokladny K, Zuhl MN, Moseley PL. Intestinal epithelial barrier function and tight junction proteins with heat and exercise. J Appl Physiol (1985). 2016; 120(6): 692–701.
- Crawford CK, Lopez Cervantes V, Quilici ML, et al. Inflammatory cytokines directly disrupt the bovine intestinal epithelial barrier. Sci Rep. 2022; 12(1): 14578.
- Shil A, Olusanya O, Ghufoor Z, et al. Artificial sweeteners disrupt tight junctions and barrier function in the intestinal epithelium through activation of the sweet taste receptor, T1R3. Nutrients. 2020; 12(6): 1862.
- Xia F, Li Y, Deng L, et al. Alisol B 23-acetate ameliorates lipopolysaccharide-induced intestinal barrier dysfunction by inhibiting TLR4-NOX1/ROS signaling pathway in caco-2 cells. Front Pharmacol. 2022; 13: 911196.
- Tian Na, Hu L, Lu Y, et al. TKT maintains intestinal ATP production and inhibits apoptosis-induced colitis. Cell Death Dis. 2021; 12(10): 853.
- Wang G, Xu B, Shi F, et al. Protective effect of methane-rich saline on acetic acid-induced ulcerative colitis via blocking the TLR4/NF-B/MAPK pathway and promoting IL-10/JAK1/STAT3-mediated anti-inflammatory response. Oxid Med Cell Longev. 2019; 2019: 7850324.
- Wang J, Zhang C, Guo C, et al. Chitosan ameliorates dss-induced ulcerative colitis mice by enhancing intestinal barrier function and improving microflora. Int J Mol Sci. 2019; 20(22): 5751.
- Gu P, Zhu L, Liu Y, et al. Protective effects of paeoniflorin on TNBS-induced ulcerative colitis through inhibiting NF-kappaB pathway and apoptosis in mice. Int Immunopharmacol. 2017; 50: 152–160.
- Liu B, Piao X, Niu W, et al. Kuijieyuan decoction improved intestinal barrier injury of ulcerative colitis by affecting TLR4-dependent PI3K/AKT/NF-κB oxidative and inflammatory signaling and gut microbiota. Front Pharmacol. 2020; 11: 1036.
- Hoy SM, Keating GM. Dexmedetomidine: a review of its use for sedation in mechanically ventilated patients in an intensive care setting and for procedural sedation. Drugs. 2011; 71(11): 1481–1501.
- Beera BK. The effect of perioperative dexmedetomidine on postoperative bowel function recovery in adult patients receiving general anaesthesia: a systematic review and meta-analysis of randomised controlled trials. Minerva Anestesiol. 2022; 88(1-2): 51–61.
- Yeh YC, Wu CY, Cheng YJ, et al. Effects of dexmedetomidine on intestinal microcirculation and intestinal epithelial barrier in endotoxemic rats. Anesthesiology. 2016; 125(2): 355–367.
- Wang ZX, Huang CY, Hua YP, et al. Dexmedetomidine reduces intestinal and hepatic injury after hepatectomy with inflow occlusion under general anaesthesia: a randomized controlled trial. Br J Anaesth. 2014; 112(6): 1055–1064.
- Zhang YN, Liu ZM, Wen SH, et al. Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology. 2012; 116(5): 1035–1046.
- Karaca O, Doğan G. The effects of dexmedetomidine in increased intestinal permeability after traumatic brain injury: an experimental study. Ulus Travma Acil Cerrahi Derg. 2020; 26(1): 15–20.
- Han X, Wu Y, Zhuang Y, et al. Dexmedetomidine reduces dextran sulfate sodium (DSS)-induced NCM460 cell inflammation and barrier damage by inhibiting RhoA/ROCK signaling pathway. Allergol Immunopathol (Madr). 2022; 50(3): 85–92.
- Tao J, Huang Z, Wang Y, et al. Ethanolic extract from alleviates dss-induced intestinal inflammation and intestinal barrier dysfunction by inhibiting the tlr4/nf-κb pathway and regulating tight junction proteins. Molecules. 2022; 27(10): 3093.
- Duan C, Xu Xi, Lu X, et al. RIP3 knockdown inhibits necroptosis of human intestinal epithelial cells via TLR4/MyD88/NF-κB signaling and ameliorates murine colitis. BMC Gastroenterol. 2022; 22(1): 137.
- Liu Y, Yu Y, Zhang J, et al. The therapeutic effect of dexmedetomidine on protection from renal failure via inhibiting KDM5A in lipopolysaccharide-induced sepsis of mice. Life Sci. 2019; 239: 116868.
- Zhou J, Tan L, Xie J, et al. Characterization of brusatol self-microemulsifying drug delivery system and its therapeutic effect against dextran sodium sulfate-induced ulcerative colitis in mice. Drug Deliv. 2017; 24(1): 1667–1679.
- Yang XZ, Cheng TT, He QJ, et al. LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway. Mol Cancer. 2018; 17(1): 126.
- Liu B, Yan X, Hou Z, et al. Impact of Bupivacaine on malignant proliferation, apoptosis and autophagy of human colorectal cancer SW480 cells through regulating NF-κB signaling path. Bioengineered. 2021; 12(1): 2723–2733.
- Fan X, Zhang Y, Dong H, et al. Trilobatin attenuates the LPS-mediated inflammatory response by suppressing the NF-κB signaling pathway. Food Chem. 2015; 166: 609–615.
- Deng X, Wang Y, Tian L, et al. Anneslea fragrans Wall. ameliorates ulcerative colitis via inhibiting NF-κB and MAPK activation and mediating intestinal barrier integrity. J Ethnopharmacol. 2021; 278: 114304.
- Lührs H, Gerke T, Müller JG, et al. Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis. Scand J Gastroenterol. 2002; 37(4): 458–466.
- Hu LH, Liu JY, Yin JB. Eriodictyol attenuates TNBS-induced ulcerative colitis through repressing TLR4/NF-kB signaling pathway in rats. Kaohsiung J Med Sci. 2021; 37(9): 812–818.
- Yang QY, Ma Ll, Zhang C, et al. Exploring the mechanism of indigo naturalis in the treatment of ulcerative colitis based on tlr4/myd88/nf-κb signaling pathway and gut microbiota. Front Pharmacol. 2021; 12: 674416.
