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

• Seo KH
• Choi JW
• Jung HS
• Yoo H
• Joo JD

• KMID: 2366654
• DOI: http://doi.org/10.3346/jkms.2017.32.3.542

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.

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