Remifentanil Ameliorates Liver Ischemia-Reperfusion Injury Through Inhibition of Interleukin-18 Signaling.
BACKGROUND
Hepatic injury induced by ischemia-reperfusion (I/R) after transplantation or lobectomy is a major clinical problem. The potential benefit of remifentanil in these hepatic surgeries remains unknown. The current study investigated whether remifentanil protects the liver against I/R injury in a rat model and whether the underlying mechanism involves the modulation of interleukin (IL)-18 signaling.


METHODS
Male Sprague-Dawley rats were subjected to 45 minutes of partial hepatic ischemia followed by 6 hours of reperfusion. Then, they received an intravenous saline or remifentanil (0.4, 2, or 10 μg/kg per minute) infusion from 30 minutes before ischemia until the end of ischemia with or without previous administration of naloxone, a nonselective opioid receptor antagonist. Serum aminotransferase, hepatic morphology, and hepatic neutrophil infiltration were analyzed. The expression of hepatic IL-18; IL-18-binding protein (BP); and key cytokines downstream of IL-18 signaling were measured.


RESULTS
Remifentanil significantly decreased serum aminotransferase levels and profoundly attenuated the liver histologic damages. Liver I/R injury increased the expression of both hepatic IL-18 and IL-18BP. Although remifentanil pretreatment significantly decreased I/R-induced IL-18 expression, it further upregulated IL-18BP levels in liver tissues. The I/R-induced increases of hepatic interferon-γ, tumor necrosis factor-α and IL-1β expression, and neutrophil infiltration were also significantly reduced by remifentanil. Naloxone inhibited the remifentanil-induced downregulation of IL-18, but not the elevation of IL-18BP, and significantly attenuated its protective effects on liver I/R injury.


CONCLUSIONS
Remifentanil protects the liver against I/R injury. Modulating the hepatic IL-18/IL-18BP balance and inhibiting IL-18 signaling mediate, at least in part, the hepatoprotective effects of remifentanil.
1 Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Xiaohua
X
Liu
Zhiying
Z
Pan
Diansan
D
Su
Zhongwei
Z
Yang
Beijie
B
Zheng
Xiangrui
X
Wang
Jie
J
Tian
D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009270:Naloxone / Q000737:chemistry; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077208:Remifentanil; D015427:Reperfusion Injury / Q000628:therapy*; D015398:Signal Transduction; D000637:Transaminases / Q000097:blood
D000701:Analgesics, Opioid; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D010880:Piperidines; C118370:interleukin-18 binding protein; D009270:Naloxone; D007371:Interferon-gamma; D009195:Peroxidase; D000637:Transaminases; D000077208:Remifentanil