Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice
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-κB) through interacting with IKKα 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{sup −/−}) mice. Our results indicated that NLRC5{sup −/−} showed significantly stronger histologic damage, inflammatory response, oxidative stress and apoptosis after I/R 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/R injury, WT and NLRC5{sup −/−} mice pre-treated with DEX exhibited attenuated histological disruption, and reduced pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β and inducible nitric oxide synthase (iNOS), which was associated with the inactivated NF-κB 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{sup −/−} 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 pre-treatment. - Highlights: • NLRC5 deletion accelerated liver I/R injury by promoting inflammatory response. • DEX pre-treatment restrained inflammation-related up regulation of NLRC5 in I/R mice. • DEX inhibited I/R-induced the progression of oxidative stress in NLRC5 deficiency mice liver. • DEX suppressed LPS-induced inflammation and oxidative stress in NLRC5 deficiency hepatocytes.
- OSTI ID:
- 22719141
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 493, Issue 2; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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