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Ketamine attenuates high mobility group box-1-induced inflammatory responses in endothelial cells
Zhaohui Liu1, Zhengping Wang2, Guangwei Han3
1Department of Anesthesiology, Cangzhou Central Hospital, Hebei Medical University, Hebei, China.
Background:
High mobility group box-1 (HMGB1) acts as an inflammatory mediator and has been implicated in pathophysiological damage of vascular inflammatory diseases. Ketamine, an anesthetic agent with sedative and analgesic properties, has been shown to have potent anti-inflammatory effects in a variety of models of systemic inflammation. However, the effects of ketamine on HMGB1-mediated proinflammatory responses have not been fully investigated. In the present study, we investigated the effects of ketamine on HMGB1-activated endothelial cells and explored the underlying mechanisms.
Methods:
Human endothelial cells were incubated with or without HMGB1 (1 μg/mL) in the presence or absence of ketamine, an nuclear factor (NF)-κB inhibitor (PDTC), anti-toll-like receptor (TLR)2/4 antibody, or small interfering RNA (siRNA). The anti-inflammatory activities of ketamine were determined by measuring solute flux, leukocyte adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated endothelial cells. The effect of ketamine on TLR-2/4 and NF-κB activation was evaluated using enzyme-linked immunosorbent assays and immunofluorescence confocal microscopy assay.
Results:
We found that ketamine inhibited the HMGB1-mediated barrier disruption, neutrophil adhesion and migration, and expression of cell adhesion molecules in a dose-dependent manner. Furthermore, ketamine downregulated the TLR-2 and -4, expression in HMGB1-activated endothelial cells. Treatment with ketamine also significantly inhibited the activation of TLR2/4 and the nuclear translocation of NF-κB p50/p65. Furthermore, our study shows that the HMGB1-induced release of inflammatory mediators was suppressed by PDTC, anti-TLR2/4 antibody, and siRNA.
Conclusions:
Our study has demonstrated that ketamine exerts anti-inflammatory effects in HMGB1-mediated proinflammatory responses in a dose-dependent manner. The mechanism responsible for these effects involves the TLR2/4 and NF-κB signaling pathway.
