Immunomodulatory effects of intraoperative dexmedetomidine on T helper 1, T helper 2, T helper 17 and regulatory T cells cytokine levels and their balance: a prospective, randomised, double-blind, dose-response clinical study.

BACKGROUND: The ratio of T helper 1 (Th1) to T helper 2 (Th2) as well as T helper 17 (Th17) to regulatory T cells (Treg) represents the state and direction of immune response. Recent studies demonstrated that dexmedetomidine reduced the secretion of inflammatory cytokines. We performed this study to investigate the effect of different doses of intraoperative dexmedetomidine on the expression of Th1, Th2, T17 and Treg cytokines and their ratios. METHODS: Seventy-five patients undergoing laparoscopic cholecystectomy were randomly separated into one of three groups: the full dose group (n = 25), in which dexmedetomidine was infused with a 1.0 µg/kg loading followed by an infusion of 0.5 µg/kg/min after anaesthetic induction, or the half dose group (n = 26), in which the dose was half of that of full dose group, or the saline group (n = 24) which was control. T cell cytokines were quantified by sandwich enzyme-linked immunoassay for blood samples taken after anaesthetic induction (T0), at the end of surgery (T1), and 60 min after surgery (T2). IFN-gamma/IL-4 and IL-17/IL-10, which represent the ratio of Th1/Th2 and Th17/Treg cytokines, respectively, were calculated as indices of immune cell levels based upon serum cytokines levels in place of direct measurements. C-reactive protein (CRP) concentrations were measured on the next day following surgery. RESULTS: The full dose group was associated with higher ratios of IFN-gamma/IL-4 than those of half dose group and control [10.1 vs. 1.9 at T1 (P = 0.041) compared with half dose group, and 10.1 vs. 0.2 at T1 (P = 0.031), 7.4 vs. 0.1 at T2 (P = 0.025) compared with control]. IL-17/IL-10 ratios were higher in the full dose group than those in control [4.2 vs. 0.6 at T1 (P = 0.013), 3.0 vs. 0.3 at T2 (P = 0.011)]. The CRP levels were lower in the dexmedetomidine-treated groups in a dose-dependent manner. CONCLUSIONS: Dexmedetomidine exhibits immunomodulatory effects, shifting the Th1/Th2 and T17/Treg cytokine balance toward Th1 and T17, respectively, in a dose-dependent pattern in patients with surgical and anaesthetic stress. TRIAL REGISTRATION: Clinical Research Information Service, Republic of Korea (CRIS); KCT0000503 ; Registration date: Aug 13, 2012.

Enhanced Expression of TREK-1 Is Related with Chronic Constriction Injury of Neuropathic Pain Mouse Model in Dorsal Root Ganglion.

Neuropathic pain is a complex state showing increased pain response with dysfunctional inhibitory neurotransmission. The TREK family, one of the two pore domain K⁺ (K2P) channel subgroups were focused among various mechanisms of neuropathic pain. These channels influence neuronal excitability and are thought to be related in mechano/thermosensation. However, only a little is known about the expression and role of TREK-1 and TREK-2, in neuropathic pain. It is performed to know whether TREK-1 and/ or 2 are positively related in dorsal root ganglion (DRG) of a mouse neuropathic pain model, the chronic constriction injury (CCI) model. Following this purpose, Reverse Transcription Polymerase Chain Reaction (RT-PCR) and western blot analyses were performed using mouse DRG of CCI model and compared to the sham surgery group. Immunofluorescence staining of isolectin- B4 (IB4) and TREK were performed. Electrophysiological recordings of single channel currents were analyzed to obtain the information about the channel. Interactions with known TREK activators were tested to confirm the expression. While both TREK-1 and TREK-2 mRNA were significantly overexpressed in DRG of CCI mice, only TREK-1 showed significant increase (~9 fold) in western blot analysis. The TREK-1-like channel recorded in DRG neurons of the CCI mouse showed similar current-voltage relationship and conductance to TREK-1. It was easily activated by low pH solution (pH 6.3), negative pressure, and riluzole. Immunofluorescence images showed the expression of TREK-1 was stronger compared to TREK-2 on IB4 positive neurons. These results suggest that modulation of the TREK-1 channel may have beneficial analgesic effects in neuropathic pain patients.

Effects of dexmedetomidine on the ratio of T helper 1 to T helper 2 cytokines in patients undergoing laparoscopic cholecystectomy.

STUDY OBJECTIVES: To investigate the effect of dexmedetomidine on T helper 1 (Th1) and T helper 2 (Th2) cytokines and their ratio during and after surgery. DESIGN: Single-blinded, randomized, placebo-controlled clinical comparison study. SETTING: Academic medical center. PATIENTS: 46 adult, ASA physical status 1 and 2 patients scheduled for laparoscopic cholecystectomy. INTERVENTIONS: Patients were randomized to two groups: the dexmedetomidine group (n = 23), in which dexmedetomidine was infused with a 1.0 µg/kg loading dose followed by infusion of 0.5 µg/kg/h; or the saline group (n = 23). MEASUREMENTS: Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) as Th1 and Th2 cytokines, respectively, were quantified three times: after induction of anesthesia (T0), at the end of peritoneal closure (T1), and 60 minutes after surgery (T2). The IFN-gamma/IL-4 ratio was then calculated. MAIN RESULTS: The dexmedetomidine group displayed higher levels of IFN-gamma at T1 and T2 (42.30 pg/dL vs 6.91 pg/dL at T1 [P = 0.025]; 40.51 pg/dL vs 8.29 pg/dL at T2 [P = 0.030]) than the saline group. The dexmedetomidine group was also associated with higher ratios of IFN-gamma/IL-4 (1.22 vs 0.32, respectively, at T1 [P = 0.012]; 1.53 vs 0.13, respectively, at T2 [P = 0.012]). CONCLUSIONS: Dexmedetomidine plays an immunomodulatory role, shifting the Th1/Th2 cytokine balance toward Th1 in patients with surgical and anesthetic stress.