J Korean Med Sci.  2017 Mar;32(3):542-551. 10.3346/jkms.2017.32.3.542.

The Effects of Remifentanil on Expression of High Mobility Group Box 1 in Septic Rats

Affiliations
  • 1Department of Anesthesiology and Pain Medicine, Saint Vincent's Hospital, The College of Medicine, The Catholic University of Korea, Suwon, Korea. joojd@catholic.ac.kr

Abstract

High mobility group box 1 (HMGB1) is a pivotal mediator of sepsis progression. Remifentanil, an opioid agonist, has demonstrated anti-inflammatory effects in septic mice. However, it is not yet known whether remifentanil affects the expression of HMGB1. We investigated the effects of remifentanil on HMGB1 expression and the underlying mechanism in septic rats. Forty-eight male Sprague-Dawley rats were randomly divided into 3 groups; a sham group, a cecal ligation and puncture (CLP) group, and a CLP with remifentanil treatment (Remi) group. The rat model of CLP was used to examine plasma concentrations of proinflammatory cytokines, tissue HMGB1 mRNA and the activity of nuclear factor (NF)-κB in the liver, lungs, kidneys, and ileum. Pathologic changes and immunohistochemical staining of NF-κB in the liver, lungs, and kidneys tissue were observed. We found that remifentanil treatment suppressed the level of serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α 6 hours after CLP, and serum HMGB1 24 hours after CLP. HMGB1 mRNA levels and the activity of NF-κB in multiple organs decreased by remifentanil treatment 24 hours after CLP. Remifentanil treatment also attenuated nuclear expression of NF-κB in immunohistochemical staining and mitigated pathologic changes in multiple organs. Altogether, these results suggested that remifentanil inhibited expression of HMGB1 in vital organs and release of HMGB1 into plasma. The mechanism was related to the inhibitory effect of remifentanil on the release of proinflammatory cytokines and activation of NF-κB.

Keyword

HMGB1 Protein; Inflammation; NF-κB; Remifentanil; Sepsis

MeSH Terms

Animals
Cytokines
HMGB1 Protein
Humans
Ileum
Inflammation
Interleukins
Kidney
Ligation
Liver
Lung
Male
Mice
Models, Animal
Plasma
Punctures
Rats*
Rats, Sprague-Dawley
RNA, Messenger
Sepsis
Tumor Necrosis Factor-alpha
Cytokines
HMGB1 Protein
Interleukins
RNA, Messenger
Tumor Necrosis Factor-alpha

Figure

  • Fig. 1 Effects of remifentanil treatment in inflammatory cytokines release 6 and 24 hours after sham/CLP operation. Serum TNF-α, IL-6, and HMGB1 concentration were analyzed by ELISA in rats subjected to sham/CLP operation. Data were presented as mean ± SD (n = 8). TNF = tumor necrosis factor, IL = interleukin, HMGB1 = high mobility group box 1, ELISA = enzyme linked immunosorbent assay, SD = standard deviation, Sham = sham operation group, CLP = cecal ligation and puncture with normal saline group, Remi = cecal ligation and puncture with remifentanil treatment group. *P < 0.05 vs. sham; †P < 0.05 vs. CLP.

  • Fig. 2 The expressions of HMGB1 mRNA in tissues of rats in each group 24 hours after sham/CLP operation. Liver, lungs, kidneys, and ileum were collected 24 hours after surgery. HMGB1 mRNA expression in multiple organs were measured by real-time PCR. Data were presented as mean ± SD (n = 8). HMGB1 = high mobility group box 1, PCR = polymerase chain reaction, SD = standard deviation, Sham = sham operation group, CLP = cecal ligation and puncture with normal saline group, Remi = cecal ligation and puncture with remifentanil treatment group. *P < 0.05 vs. sham; †P < 0.05 vs. CLP.

  • Fig. 3 Effects of remifentanil treatment on activity of NF-κB in organs of septic rats 24 hours after CLP operation. (A) Liver, Lungs, kidneys, and ileum were collected 24 hours after sham/CLP operation and NF-κB p65 activation was analyzed by Western blot. Data were presented as mean ± SD (n = 8). (B) Immunohistochemical staining of NF-κB p65 in liver, lungs, and kidneys from rats subjected to sham/CLP operation 24 hours after surgery. Original magnification: × 400. NF = nuclear factor, SD = standard deviation, Sham = sham operation group, CLP = cecal ligation and puncture with normal saline group, Remi = cecal ligation and puncture with remifentanil treatment group. *P < 0.05 vs. sham; †P < 0.05 vs. CLP.

  • Fig. 4 H & E stained sections of liver, lungs and kidneys from rats subjected to sham/CLP operation 6 hours and 24 hours after surgery. Original magnification: × 400. H & E = hematoxylin and eosin, Sham = sham operation group, CLP = Cecal ligation and puncture with normal saline group, Remi = cecal ligation and puncture with remifentanil treatment group.


Reference

1. Sagy M, Al-Qaqaa Y, Kim P. Definitions and pathophysiology of sepsis. Curr Probl Pediatr Adolesc Health Care. 2013; 43:260–263.
2. van Beijnum JR, Buurman WA, Griffioen AW. Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis. 2008; 11:91–99.
3. Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med. 2004; 255:320–331.
4. Gibot S, Massin F, Cravoisy A, Barraud D, Nace L, Levy B, Bollaert PE. High-mobility group box 1 protein plasma concentrations during septic shock. Intensive Care Med. 2007; 33:1347–1353.
5. Hou LC, Qin MZ, Zheng LN, Lu Y, Wang Q, Peng DR, Yu XP, Xin YC, Ji GL, Xiong LZ. Severity of sepsis is correlated with the elevation of serum high-mobility group box 1 in rats. Chin Med J (Engl). 2009; 122:449–454.
6. Sundén-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, Lee ML, Andersson J, Tokics L, Treutiger CJ. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med. 2005; 33:564–573.
7. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999; 285:248–251.
8. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA. 2004; 101:296–301.
9. Hofbauer R, Frass M, Gmeiner B, Sandor N, Schumann R, Wagner O, Kaye AD. Effects of remifentanil on neutrophil adhesion, transmigration, and intercellular adhesion molecule expression. Acta Anaesthesiol Scand. 2000; 44:1232–1237.
10. Sacerdote P, Gaspani L, Rossoni G, Panerai AE, Bianchi M. Effect of the opioid remifentanil on cellular immune response in the rat. Int Immunopharmacol. 2001; 1:713–719.
11. Zongze Z, Jia Z, Chang C, Kai C, Yanlin W. Protective effects of remifentanil on septic mice. Mol Biol Rep. 2010; 37:2803–2808.
12. Zhang Y, Du Z, Zhou Q, Wang Y, Li J. Remifentanil attenuates lipopolysaccharide-induced acute lung injury by downregulating the NF-kappaB signaling pathway. Inflammation. 2014; 37:1654–1660.
13. Dejager L, Pinheiro I, Dejonckheere E, Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol. 2011; 19:198–208.
14. Ayala A, Chaudry IH. Immune dysfunction in murine polymicrobial sepsis: mediators, macrophages, lymphocytes and apoptosis. Shock. 1996; 6:Suppl 1. S27–38.
15. Gårdlund B, Sjölin J, Nilsson A, Roll M, Wickerts CJ, Wretlind B. Plasma levels of cytokines in primary septic shock in humans: correlation with disease severity. J Infect Dis. 1995; 172:296–301.
16. 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; 67:6603–6610.
17. 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; 74:1704–1710.
18. Song XM, Wang YL, Li JG, Wang CY, Zhou Q, Zhang ZZ, Liang H. Effects of propofol on pro-inflammatory cytokines and nuclear factor kappaB during polymicrobial sepsis in rats. Mol Biol Rep. 2009; 36:2345–2351.
19. Xu L, Bao H, Si Y, Wang X. Effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice. Inflamm Res. 2013; 62:507–514.
20. Huang LF, Yao YM, Sheng ZY. Novel insights for high mobility group box 1 protein-mediated cellular immune response in sepsis: a systemic review. World J Emerg Med. 2012; 3:165–171.
21. Karlsson S, Pettilä V, Tenhunen J, Laru-Sompa R, Hynninen M, Ruokonen E. HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis. Intensive Care Med. 2008; 34:1046–1053.
22. Ji MH, Zhu XL, Liu FF, Li GM, Tian M, Wu J, Fan YX, Li N, Yang JJ. Alpha 2A-adrenoreceptor blockade improves sepsis-induced acute lung injury accompanied with depressed high mobility group box-1 levels in rats. Cytokine. 2012; 60:639–645.
23. Wang HL, Xing YQ, Xu YX, Rong F, Lei WF, Zhang WH. The protective effect of lidocaine on septic rats via the inhibition of high mobility group box 1 expression and NF-kappaB activation. Mediators Inflamm. 2013; 2013:570370.
24. Zhang LT, Yao YM, Lu JQ, Yan XJ, Yu Y, Sheng ZY. Sodium butyrate prevents lethality of severe sepsis in rats. Shock. 2007; 27:672–677.
25. Li X, Stark GR. NFκB-dependent signaling pathways. Exp Hematol. 2002; 30:285–296.
26. Sharp BM, Roy S, Bidlack JM. Evidence for opioid receptors on cells involved in host defense and the immune system. J Neuroimmunol. 1998; 83:45–56.
27. Mellon RD, Bayer BM. Evidence for central opioid receptors in the immunomodulatory effects of morphine: review of potential mechanism(s) of action. J Neuroimmunol. 1998; 83:19–28.
28. Hyejin J, Mei L, Seongheon L, Cheolwon J, Seokjai K, Hongbeom B, Minsun K, Sungsu C, Sanghyun K. Remifentanil attenuates human neutrophils activation induced by lipopolysaccharide. Immunopharmacol Immunotoxicol. 2013; 35:264–271.
29. Ke JJ, Zhan J, Feng XB, Wu Y, Rao Y, Wang YL. A comparison of the effect of total intravenous anaesthesia with propofol and remifentanil and inhalational anaesthesia with isoflurane on the release of pro- and anti-inflammatory cytokines in patients undergoing open cholecystectomy. Anaesth Intensive Care. 2008; 36:74–78.
30. von Dossow V, Luetz A, Haas A, Sawitzki B, Wernecke KD, Volk HD, Spies CD. Effects of remifentanil and fentanyl on the cell-mediated immune response in patients undergoing elective coronary artery bypass graft surgery. J Int Med Res. 2008; 36:1235–1247.
31. Winterhalter M, Brandl K, Rahe-Meyer N, Osthaus A, Hecker H, Hagl C, Adams HA, Piepenbrock S. Endocrine stress response and inflammatory activation during CABG surgery. A randomized trial comparing remifentanil infusion to intermittent fentanyl. Eur J Anaesthesiol. 2008; 25:326–335.
32. Cho SS, Rudloff I, Berger PJ, Irwin MG, Nold MF, Cheng W, Nold-Petry CA. Remifentanil ameliorates intestinal ischemia-reperfusion injury. BMC Gastroenterol. 2013; 13:69.
33. Ge Y, Hu S, Zhang Y, Wang W, Xu Q, Zhou L, Mao H. Levobupivacaine inhibits lipopolysaccharide-induced high mobility group box 1 release in vitro and in vivo. J Surg Res. 2014; 192:582–591.
34. Yu M, Shao D, Liu J, Zhu J, Zhang Z, Xu J. Effects of ketamine on levels of cytokines, NF-kappaB and TLRs in rat intestine during CLP-induced sepsis. Int Immunopharmacol. 2007; 7:1076–1082.
35. Breen D, Karabinis A, Malbrain M, Morais R, Albrecht S, Jarnvig IL, Parkinson P, Kirkham AJ. Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial [ISRCTN47583497]. Crit Care. 2005; 9:R200–R210.
36. Battershill AJ, Keating GM. Remifentanil: a review of its analgesic and sedative use in the intensive care unit. Drugs. 2006; 66:365–385.
37. Zhang Z, Zhang L, Zhou C, Wu H. Ketamine inhibits LPS-induced HGMB1 release in vitro and in vivo. Int Immunopharmacol. 2014; 23:14–26.
Full Text Links
  • JKMS
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr