Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 17, Issue 7, Pages -Publisher
MDPI AG
DOI: 10.3390/ijms17070995
Keywords
dexmedetomidine; ischemia-reperfusion injury; liver transplantation; TLR4; NF-B; (2A)-adrenoceptor subtype
Funding
- Natural Science Foundation of China [81471892]
- Natural Science Foundation of Guangdong Province, China [2014A030313199]
- Science and Technology Project Foundation of Guangdong Province, China [2008B030301053, 2013B021800181]
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Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-B) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via (2)-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The authors aimed to examine whether pretreatment with Dex produces hepatic protection and investigate the influence of Dex on TLR4/NF-B signaling. Dex was given via intraperitoneal injection 30 min prior to orthotopic autologous liver transplantation (OALT) in rats, and three (2)-adrenoceptor antagonists including atipamezole (a nonselective (2) receptor blocker), ARC-239 (a specific (2B/C) blocker) and BRL-44408 (a specific (2A) blocker) were injected intraperitoneally 10 min before Dex administration. Histopathologic evaluation of the liver and the measurement of serum alanine aminotransferase activity, TLR4/NF-B expression in the liver, and pro-inflammatory factors (serum tumor necrosis factor-, interleukin-1 and hepatic myeloperoxidase) concentrations were performed 8 h after OALT. Dex ameliorated liver injury after OALT probably by suppressing the TLR4/NF-B pathway and decreasing inflammatory mediator levels. The protective effects of Dex were reversed by atipamezole and BRL-44408, but not by ARC-239, suggesting that these effects were mediated in part by the (2A) subtype. In conclusion, Dex attenuates liver injury partly via the (2A)-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-B pathway.
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