Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice
Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice
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DOI：
10.1016/j.bbrc.2017.08.017
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发表时间：
2017-11-18
影响因子：
3.1
通讯作者：
Ma, Chuan-Gen
中科院分区：
文献类型：
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作者：
Chen, Zong;Ding, Tao;Ma, Chuan-Gen
肝脏缺血/再灌注（I/R）损伤可能是肝脏手术和移植的并发症。没有特定的治疗策略可以减轻 I/R 损伤。 NOD-、LRR-和 CARD contains 5 (NLRC5) 是 NOD 样蛋白家族的成员，已被认为通过与 IKKa 相互作用并阻断其磷酸化来负向调节核因子 kappa B (NF-kappa B)。右美托咪定（DEX）已被证明可以减轻肝损伤。在本研究中，我们研究了 DEX 预处理对野生型 (WT) 和 NLRC5 敲除 (NLRC5(-/-)) 小鼠肝 I/R 损伤的影响。我们的结果表明，与WT组小鼠相比，NLRC5(-/-)在I/12后表现出明显更强的组织学损伤、炎症反应、氧化应激和细胞凋亡，表明NLRC5对肝脏I/R损伤的保护作用。重要的是，DEX 预处理减少了 I/R 诱导的 NLRC5 增加。肝 I/12 损伤后，用 DEX 预处理的 WT 和 NLRC5(-/-) 小鼠表现出组织学破坏减弱，促炎介质减少，包括肿瘤坏死因子-α (TNF-α)、白细胞介素 (IL)-6、IL-1 β 和诱导型一氧化氮合酶 (iNOS)，这些介质与失活的 NF-κ B 通路相关。此外，在 DEX 治疗的 I/R 损伤小鼠中观察到氧化应激和细胞凋亡受到抑制，可能是通过增强核因子红细胞 2 相关因子 2 (Nrf2)、减少丝裂原激活蛋白激酶 (MAPK) 和 Caspase-3/聚 (ADP-核糖) 聚合酶 (PARP) 途径。在体外，结果在用或不用 DEX 预处理的 WT 和 NLRC5(-/-) 肝细胞中得到进一步证实。总之，研究结果表明，NLRC5 的缺乏会导致更严重的肝脏 I/R 损伤，而这种损伤可以通过 DEX 预处理来缓解。 (C) 2017 Elsevier Inc. 保留所有权利。
Hepatic ischemia/reperfusion (I/R) injury could arise as a complication of liver surgery and transplantation. No specific therapeutic strategies are available to attenuate I/R injury. NOD-, LRR-and CARD containing 5 (NLRC5), a member of the NOD-like protein family, has been suggested to negatively regulate nuclear factor kappa B (NF-kappa B) through interacting with IKKa and blocking their phosphorylation. Dexmedetomidine (DEX) has been shown to attenuate liver injury. In the current study, we investigated the pre-treatment of DEX on hepatic I/R injury in wild type (WT) and NLRC5 knockout (NLRC5(-/-)) mice. Our results indicated that NLRC5(-/-) showed significantly stronger histologic damage, inflammatory response, oxidative stress and apoptosis after I/12 compared to the WT group of mice, indicating the protective role of NLRC5 against liver I/R injury. Importantly, I/R-induced increase of NLRC5 was reduced by DEX pre-treatment. After hepatic I/12 injury, WT and NLRC5(-/-) mice pre-treated with DEX exhibited attenuated histological disruption, and reduced pro-inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-1 beta and inducible nitric oxide synthase (iNOS), which was associated with the inactivated NF-kappa B pathway. Moreover, suppression of oxidative stress and apoptosis was observed in DEX-treated mice with I/R injury, probably through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2), reducing mitogen-activated protein kinases (MAPKs) and Caspase-3/poly (ADP-ribose) polymerase (PARP) pathways. In vitro, the results were further confirmed in WT and NLRC5(-/-) hepatocytes pre-treated with or without DEX. Together, the findings illustrated that lack of NLRC5 resulted in severer liver I/R injury, which could be alleviated by DEX pretreatment. (C) 2017 Elsevier Inc. All rights reserved.