Skip to main content

Advertisement

SpringerLink
Log in

Effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

We investigated whether dexmedetomidine provided protective effects on cecal ligation and puncture (CLP)–induced septic mice, through suppressing the expression of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6)] and high mobility group box 1 (HMGB1).

Methods

The model of sepsis was set up by CLP in 136 male BALB/c mice (40 mice for survival studies and 96 for cytokine studies) which were divided into four groups, including a C, CLP, DEX + CLP and CLP + DEX group. The serum levels of TNF-α, IL-6 and HMGB1 were detected at 6, 12, 24 and 48 h after operations, and lung HMGB1 mRNA were analyzed at 24 and 48 h. The mortality rates were calculated 7 days after the operations.

Results

The mortality rates 7 days after operations were significantly lower in the CLP + DEX (50 %) and DEX + CLP (30 %) groups than in the CLP group (90 %). Serum concentrations of IL-6 and TNF-α decreased significantly in dexmedetomidine administration groups compared with the CLP group. The levels of HMGB1 and lung HMGB1 mRNA were lower in the dexmedetomidine administration groups than in the CLP group. There was a significant correlation between lung HMGB1 mRNA and serum HMGB1(r = 0.858).

Conclusions

Dexmedetomidine could reduce the mortality rate and inhibit pro-inflammatory cytokine responses during polymicrobial sepsis in mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis-associated disseminated intravascular coagulation and thromboembolic disease. Mediterr J Hematol Infect Dis. 2010;2:e2010024.

    Article  PubMed  Google Scholar 

  2. American College of Chest Physicians/Society of Critical Care Medicine Consensu Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–74.

    Article  Google Scholar 

  3. Ozdulger A, Cinel I, Koksel O, Cinel L, Avlan D, Unlu A, Okcu H, Dikmengil M, Oral U. The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model. Shock. 2003;19:366–72.

    Article  PubMed  CAS  Google Scholar 

  4. Sun BW, Shi GS, Zhang P, Zou XQ, Chen X. Inhibitive effect of exogenous carbon monoxide-releasing molecules 2 on tissue factor expression in sepsis. Zhonghua Shao Shang Za Zhi. 2009;25:111–4.

    PubMed  Google Scholar 

  5. Bredan AS, Cauwels A. Is there NO treatment for severe sepsis? Libyan J Med. 2008;3:34–8.

    Article  Google Scholar 

  6. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. Intensive Care Med. 2008;34:17–60.

    Article  PubMed  Google Scholar 

  7. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285:248–51.

    Article  PubMed  CAS  Google Scholar 

  8. Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ. HMG-1 as a mediator of acute lung inflammation. J Immunol. 2000;165:2950–4.

    PubMed  CAS  Google Scholar 

  9. Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med. 2004;255:320–31.

    Article  PubMed  CAS  Google Scholar 

  10. Ueno H, Matsuda T, Hashimoto S, Amaya F, Kitamura Y, Tanaka M, Kobayashi A, Maruyama I, Yamada S, Hasegawa N, Soejima J, Koh H, Ishizaka A. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am J Respir Crit Care Med. 2004;170:1310–6.

    Article  PubMed  Google Scholar 

  11. Yang H, Wang H, Czura CJ, Tracey KJ. The cytokine activity of HMGB1. J Leukoc Biol. 2005;78:1–8.

    Article  PubMed  CAS  Google Scholar 

  12. Kim JY, Park JS, Strassheim D, Douglas I, Diaz del Valle F, Asehnoune K, Mitra S, Kwak SH, Yamada S, Maruyama I, Ishizaka A, Abraham E. HMGB1 contributes to the development of acute lung injury after hemorrhage. Am J Physiol Lung Cell Mol Physiol. 2005;288:L958–65.

    Article  PubMed  CAS  Google Scholar 

  13. Virtanen R, Savola JM, Saano V, Nyman L. Characterization of the selectivity, specificity and potency of medetomidine as an alpha2-adrenoceptor agonist. Eur J Pharmacol. 1988;150:9–14.

    Article  PubMed  CAS  Google Scholar 

  14. Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, Vedio A, Singer M, Feneck R, Treacher D, Willatts SM, Grounds RM. Preliminary UK experience of dexmedetomidine a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54:1136–42.

    Article  PubMed  CAS  Google Scholar 

  15. Bachand RT, List W, Etropolski M, Martin E. A phase III study evaluating dexmedetomidine for sedation in postoperative patients. Anesthesiology. 1999;91:A296.

    Google Scholar 

  16. Triltsch AE, Welte M, von Homeyer P, Grosse J, Genähr A, Moshirzadeh M, Sidiropoulos A, Konertz W, Kox WJ, Spies CD. Bispectral index-guided sedation with dexmedetomidine in intensive care: a prospective, randomized, double blind, placebocontrolled phase II study. Crit Care Med. 2002;30:1007–14.

    Article  PubMed  CAS  Google Scholar 

  17. Bonnet F, Boico O, Rostaing S, Loriferne JF, Saada M. Clonodine-induced analgesia in postoperative patients: epidural versus intramuscular administration. Anesthesiology. 1990;72:423–7.

    Article  PubMed  CAS  Google Scholar 

  18. Sezer A, Memiş D, Usta U, Süt N. The effect of dexmedetomidine on liver histopathology in a rat sepsis model: an experimental pilot study. Ulus Travma Acil Cerrahi Derg. 2010;16:108–12.

    PubMed  Google Scholar 

  19. Taniguchi T, Kidani Y, Kanakura H, Takemoto Y, Yamamoto K. Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats. Crit Care Med. 2004;32:1322–6.

    Article  PubMed  CAS  Google Scholar 

  20. Memiş D, Hekimoğlu S, Vatan I, Yandim T, Yüksel M, Süt N. Effects of midazolam and dexmedetomidine on inflammatory responses and gastric intramucosal pH to sepsis, in critically ill patients. Br J Anaesth. 2007;98:550–2.

    Article  PubMed  Google Scholar 

  21. Otero-Antón E, González-Quintela A, López-Soto A, López-Ben S, Llovo J, Pérez LF. Cecal ligation and puncture as a model of sepsis in the rat: influence of the puncture size on mortality, bacteremia, endotoxemia and tumor necrosis factor alpha levels. Eur Surg Res. 2001;33:77–9.

    Article  PubMed  Google Scholar 

  22. Heuer JG, Bailey DL, Sharma GR, Zhang T, Ding C, Ford A, Stephens EJ, Holmes KC, Grubbs RL, Fynboe KA, Chen YF, Jakubowski JA. Cecal ligation and puncture with total parenteral nutrition: a clinically relevant model of the metabolic, hormonal, and inflammatory dysfunction associated with critical illness. J Surg Res. 2004;121:178–86.

    Article  PubMed  CAS  Google Scholar 

  23. Liaw WJ, Chen TH, Lai ZZ, Chen SJ, Chen A, Tzao C, Wu JY, Wu CC. Effects of a membrane-permeable radical scavenger, Tempol, on intraperitoneal sepsis-induced organ injury in rats. Shock. 2005;23:88–96.

    Article  PubMed  CAS  Google Scholar 

  24. Nasraway SA. The problems and challenges of immunotherapy in sepsis. Chest. 2003;123:451S–9S.

    Article  PubMed  CAS  Google Scholar 

  25. Wheeler DS, Zingarelli B, Wheeler WJ, Wong HR. Novel pharmacologic approaches to the management of sepsis: targeting the host inflammatory response. Recent Pat Inflamm Allergy Drug Discov. 2009;3:96–112.

    Article  PubMed  CAS  Google Scholar 

  26. Hagiwara S, Iwasaka H, Matsumoto S, Hasegawa A, Yasuda N, Noguchi T. In vivo and in vitro effects of the anticoagulant, thrombomodulin, on the inflammatory response in rodent models. Shock. 2010;33:282–8.

    Article  PubMed  CAS  Google Scholar 

  27. Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T. High dose antithrombin III inhibits HMGB1 and improves endotoxin-induced acute lung injury in rats. Intensive Care Med. 2008;34:361–7.

    Article  PubMed  CAS  Google Scholar 

  28. Straub RH, Herrmann M, Berkmiller G, Frauenholz T, Lang B, Schölmerich J, Falk W. Neuronal regulation of interleukin 6 secretion in murine spleen: adrenergic and opioidergic control. J Neurochem. 1997;68:1633–9.

    Article  PubMed  CAS  Google Scholar 

  29. Maes M, Lin A, Kenis G, Egyed B, Bosmans E. The effects of noradrenaline and alpha-2 adrenoceptor agents on the production of monocytic products. Psychiatry Res. 2000;96:245–53.

    Article  PubMed  CAS  Google Scholar 

  30. Szelenyi J, Kiss JP, Vizi ES. Differential involvement of sympathetic nervous system and immune system in the modulation of TNF-alpha production by alpha2- and betaadrenoceptors in mice. J Neuroimmunol. 2000;103:34–40.

    Article  PubMed  CAS  Google Scholar 

  31. Venn RM, Bryant A, Hall GM, Grounds RM. Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in post-operative patients needing sedation in the intensive care unit. Br J Anaesth. 2001;86:650–6.

    Article  PubMed  CAS  Google Scholar 

  32. Taniguchi T, Kurita A, Kobayashi K, Yamamoto K, Inaba H. Dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats. J Anesth. 2008;22:221–8.

    Article  PubMed  Google Scholar 

  33. Wakabayashi G, Gelfard JA, Jung WK, Connolly RJ, Burke JF, Dinarello CA. Staphylococcus epidermids induces complement activation, tumor necrosis factor and interleukin-1, a shock like state and tissue injury in rabbits without endotoxemia. Comparison to Escherichia coil. J Clin Invest. 1991;87:1925–35.

    Article  PubMed  CAS  Google Scholar 

  34. Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med. 1993;119:771–8.

    Article  PubMed  CAS  Google Scholar 

  35. Natanson C, Eichenholz PW, Danner RL, Eichacker PQ, Hoffman WD, Kuo GC, Banks SM, MacVittie TJ, Parrillo JE. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med. 1989;169:823–32.

    Article  PubMed  CAS  Google Scholar 

  36. Remick DG, Bolgos GR, Siddiqui J, Shin J, Nemzek JA. Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock. 2002;17:463–7.

    Article  PubMed  Google Scholar 

  37. Beutler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987;316:379–85.

    Article  PubMed  CAS  Google Scholar 

  38. Ebong S, Call D, Nemzek J, Bolgos G, Newcomb D, Remick D. Immunopathologic alterations in murine models of sepsis of increasing severity. Infect Immun. 1999;67:6603–10.

    PubMed  CAS  Google Scholar 

  39. Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. J Exp Med. 1989;169:333–8.

    Article  PubMed  CAS  Google Scholar 

  40. Hack CE, De Groot ER, Felt-Bersma RJ, Nuijens JH, Strack Van Schijndel RJ, Eerenberg-Belmer AJ, Thijs LG, Aarden LA. Increased plasma levels of interleukin-6 in sepsis. Blood. 1989;74:1704–10.

    PubMed  CAS  Google Scholar 

  41. Riedemann NC, Neff TA, Guo RF, Bernacki KD, Laudes IJ, Sarma JV, Lambris JD, Ward PA. Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J Immunol. 2003;170:503–7.

    PubMed  CAS  Google Scholar 

  42. Yang H, Tracey KJ. Targeting HMGB1 in inflammation. Biochim Biophys Acta. 2010;1799:149–56.

    Article  PubMed  CAS  Google Scholar 

  43. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ. High mobility group 1 protein (HMGB1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 2000;192:565–70.

    Article  PubMed  CAS  Google Scholar 

  44. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.

    Article  PubMed  CAS  Google Scholar 

  45. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49.

    Article  PubMed  CAS  Google Scholar 

  46. Shao YM, Yao HG, Liang XZ, Xia YH. Relation between level of expression of high mobility group protein B1 in hepatic tissue with the severity and prognosis of sepsis in rats. Chin Crit Care Med. 2006;18:668–72.

    CAS  Google Scholar 

  47. Gu J, Sun P, Zhao H, Watts HR, Sanders RD, Terrando N, Xia P, Maze M, Ma D. Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice. Crit Care. 2011;15:R153.

    Article  PubMed  Google Scholar 

  48. Krishnan J, Selvarajoo K, Tsuchiya M, Lee G, Choi S. Toll-like receptor signal transduction. Exp Mol Med. 2007;39:421–38.

    Article  PubMed  CAS  Google Scholar 

  49. Mollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR. Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock. 2006;26:430–7.

    Article  PubMed  CAS  Google Scholar 

  50. O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64.

    Article  PubMed  Google Scholar 

  51. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–80.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China

    Li Xu, Hongguang Bao, Yanna Si & Xiaoliang Wang

Authors
  1. Li Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongguang Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanna Si
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoliang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongguang Bao.

Additional information

Responsible Editor: Artur Bauhofer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, L., Bao, H., Si, Y. et al. Effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice. Inflamm. Res. 62, 507–514 (2013). https://doi.org/10.1007/s00011-013-0604-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-013-0604-5

Keywords

Search

Navigation