Dexmedetomidine protects against endothelial injury in septic rats induced by cecal ligation and puncture by decreasing angiopoietin 2 and increasing vascular endothelial cadherin levels

Zhang,Peng; Peng,Ji; Ren,Yun-Qin; Zheng,Han; Yan,Hong

doi:10.3892/etm.2020.9543

Dexmedetomidine protects against endothelial injury in septic rats induced by cecal ligation and puncture by decreasing angiopoietin 2 and increasing vascular endothelial cadherin levels

Authors:
- Peng Zhang
- Ji Peng
- Yun-Qin Ren
- Han Zheng
- Hong Yan
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Affiliations: Department of Anesthesiology, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
Published online on: December 2, 2020 https://doi.org/10.3892/etm.2020.9543
Article Number: 111
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the protective effect of dexmedetomidine (Dex) on endothelial injury in a cecal ligation and puncture (CLP)‑induced rat model of sepsis. A total of 36 male Sprague‑Dawley rats were divided into three groups: Sham, CLP and CLP + Dex. The wet/dry (W/D) ratio of lung weight, hematoxylin and eosin (H&E) staining of lung tissue, plasma levels of angiopoietin (Ang)1 and 2, ratio of Ang2/1 and vascular endothelial (VE)‑cadherin protein expression levels in lung tissue were determined. The W/D ratio of lung tissue in the CLP + Dex group was significantly lower than that in the CLP group (P<0.01). The H&E staining results indicated that Dex treatment reduced the levels of CLP‑induced alveolar septum widening, infiltrating white blood cells and congestion, when compared with CLP alone. In addition, the expression levels of plasma Ang2 and the Ang2/1 ratio in the CLP + Dex group were significantly lower than those of the CLP rats (P<0.01). Furthermore, the level of VE‑cadherin protein in lung tissue of the CLP + Dex group was higher than that of the CLP group (P<0.05). The results indicated that Dex had a protective effect against CLP‑induced endothelial injury, through the ability to reduce expression of the endothelial injury factor Ang2 and increase the expression of the endothelial adhesion junction factor VE‑cadherin in a septic rat model. These data suggest a potential application of Dex in the clinical treatment of sepsis.

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1	Cecconi M, Evans L, Levy M and Rhodes A: Sepsis and septic shock. Lancet. 392:75–87. 2018.PubMed/NCBI View Article : Google Scholar
2	Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al: The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 315:801–810. 2016.PubMed/NCBI View Article : Google Scholar
3	Gotts JE and Matthay MA: Sepsis: Pathophysiology and clinical management. BMJ. 353(i1585)2016.PubMed/NCBI View Article : Google Scholar
4	Ince C, Mayeux PR, Nguyen T, Gomez H, Kellum JA, Ospina-Tascón GA, Hernandez G, Murray P and De Backer D: ADQI XIV Workgroup. The endothelium in sepsis. Shock. 45:259–270. 2016.PubMed/NCBI View Article : Google Scholar
5	Radeva MY and Waschke J: Mind the gap: Mechanisms regulating the endothelial barrier. Acta Physiol (Oxf): 222, 2018. doi: 10.1111/apha.12860.
6	Millar FR, Summers C, Griffiths MJ, Toshner MR and Proudfoot AG: The pulmonary endothelium in acute respiratory distress syndrome: Insights and therapeutic opportunities. Thorax. 71:462–473. 2016.PubMed/NCBI View Article : Google Scholar
7	Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR and Colin P: Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet. 56:893–913. 2017.PubMed/NCBI View Article : Google Scholar
8	Meng L, Li L, Lu S, Li K, Su Z, Wang Y, Fan X, Li X and Zhao G: The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways. Mol Immunol. 94:7–17. 2018.PubMed/NCBI View Article : Google Scholar
9	Hu H, Shi D, Hu C, Yuan X, Zhang J and Sun H: Dexmedetomidine mitigates CLP-stimulated acute lung injury via restraining the RAGE pathway. Am J Transl Res. 9:5245–5258. 2017.PubMed/NCBI
10	Li B, Li Y, Tian S, Wang H, Wu H, Zhang A and Gao C: Anti-inflammatory effects of perioperative dexmedetomidine administered as an adjunct to general anesthesia: A meta-analysis. Sci Rep. 5(12342)2015.PubMed/NCBI View Article : Google Scholar
11	Wang XW, Cao JB, Lv BS, Mi WD, Wang ZQ, Zhang C, Wang HL and Xu Z: Effect of perioperative dexmedetomidine on the endocrine modulators of stress response: A meta-analysis. Clin Exp Pharmacol Physiol. 42:828–836. 2015.PubMed/NCBI View Article : Google Scholar
12	International guidelines on animal welfare. 156: 723-723, 2005.
13	Rittirsch D, Huber-Lang MS, Flierl MA and Ward PA: Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc. 4:31–36. 2009.PubMed/NCBI View Article : Google Scholar
14	Liu X, Wang N, Wei G, Fan S, Lu Y, Zhu Y, Chen Q, Huang M, Zhou H and Zheng J: Consistency and pathophysiological characterization of a rat polymicrobial sepsis model via the improved cecal ligation and puncture surgery. Int Immunopharmacol. 32:66–75. 2016.PubMed/NCBI View Article : Google Scholar
15	Chen Q, Yi B, Ma J, Ning J, Wu L, Ma D, Lu K and Gu J: α22-adrenoreceptor modulated FAK pathway induced by dexmedetomidine attenuates pulmonary microvascular hyper-permeability following kidney injury. Oncotarget. 7:55990–56001. 2016.PubMed/NCBI View Article : Google Scholar
16	Mai SHC, Sharma N, Kwong AC, Dwivedi DJ, Khan M, Grin PM, Fox-Robichaud AE and Liaw PC: Body temperature and mouse scoring systems as surrogate markers of death in cecal ligation and puncture sepsis. Intensive Care Med Exp. 6(20)2018.PubMed/NCBI View Article : Google Scholar
17	Cox RA: Endothelin-1 and acute lung injury in sheeps with smoke inhalation and burn injury[D]. Galveston: The University of Texas,Graduate School of Biomedical Sciences: 18-19, 2003.
18	Jin Y, Yu G, Peng P, Zhang Y and Xin X: Down-regulated expression of AQP5 on lung in rat DIC model induced by LPS and its effect on the development of pulmonary edema. Pulm Pharmacol Ther. 26:661–665. 2013.PubMed/NCBI View Article : Google Scholar
19	Buras JA, Holzmann B and Sitkovsky M: Animal models of sepsis: Setting the stage. Nat Rev Drug Discov. 4:854–865. 2005.PubMed/NCBI View Article : Google Scholar
20	Cruz FF, Rocco PR and Pelosi P: Anti-inflammatory properties of anesthetic agents. Crit Care. 21(67)2017.PubMed/NCBI View Article : Google Scholar
21	Yeh YC, Wu CY, Cheng YJ, Liu CM, Hsiao JK, Chan WS, Wu ZG, Yu LC and Sun WZ: Effects of Dexmedetomidine on intestinal microcirculation and intestinal epithelial barrier in endotoxemic rats. Anesthesiology. 125:355–367. 2016.PubMed/NCBI View Article : Google Scholar
22	Miranda ML, Balarini MM and Bouskela E: Dexmedetomidine attenuates the microcirculatory derangements evoked by experimental sepsis. Anesthesiology. 122:619–630. 2015.PubMed/NCBI View Article : Google Scholar
23	Wu Y, Liu Y, Huang H, Zhu Y, Zhang Y, Lu F and Zhou C, Huang L, Li X and Zhou C: Dexmedetomidine inhibits inflammatory reaction in lung tissues of septic rats by suppressing TLR4/NF-κB pathway. Mediators Inflamm. 2013(562154)2013.PubMed/NCBI View Article : Google Scholar
24	Ma Y, Yu XY and Wang Y: Dose-related effects of dexmedetomidine on immunomodulation and mortality to septic shock in rats. World J Emerg Med. 9:56–63. 2018.PubMed/NCBI View Article : Google Scholar
25	Moss A: The angiopoietin: Tie 2 interaction: A potential target for future therapies in human vascular disease. Cytokine Growth Factor Rev. 24:579–592. 2013.PubMed/NCBI View Article : Google Scholar
26	Parikh SM: Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence. 4:517–524. 2013.PubMed/NCBI View Article : Google Scholar
27	Ricciuto DR, dos Santos CC, Hawkes M, Toltl LJ, Conroy AL, Rajwans N, Lafferty EI, Cook DJ, Fox-Robichaud A, Kahnamoui K, et al: Angiopoietin-1 and 2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med. 39:702–710. 2011.PubMed/NCBI View Article : Google Scholar
28	Han S, Lee SJ, Kim KE, Lee HS, Oh N, Park I, Ko E, Oh SJ, Lee YS, Kim D, et al: Amelioration of sepsis by TIE2 activation-induced vascular protection. Sci Transl Med. 8(335ra355)2016.PubMed/NCBI View Article : Google Scholar
29	Poli-de-Figueiredo LF, Garrido AG, Nakagawa N and Sannomiya P: Experimental models of sepsis and their clinical relevance. Shock. 30 (Suppl 1):S53–S59. 2008.PubMed/NCBI View Article : Google Scholar
30	Chousterman BG, Swirski FK and Weber GF: Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 39:517–528. 2017.PubMed/NCBI View Article : Google Scholar
31	van der Poll T, van de Veerdonk FL, Scicluna BP and Netea MG: The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 17:407–420. 2017.PubMed/NCBI View Article : Google Scholar
32	Levi M and van der Poll T: Coagulation and sepsis. Thromb Res. 149:38–44. 2017.PubMed/NCBI View Article : Google Scholar