Dexmedetomidine Attenuates LPS-Induced Monocyte-Endothelial Adherence via Inhibiting Cx43/PKC-α/NOX2/ROS Signaling Pathway in Monocytes.

Yunfei Chai,Yong Liu,Dongdong Yuan,Runying Yu,Liming Lei,Zhongming Cao

doi:10.1155/2020/2930463

Abstract

Dexmedetomidine is widely used for sedating patients in operation rooms or intensive care units. Its protective functions against oxidative stress, inflammation reaction, and apoptosis have been widely reported. In present study, we explored the effects of dexmedetomidine on monocyte-endothelial adherence. We built lipopolysaccharide- (LPS-) induced monocyte-endothelial adherence models with U937 monocytes and human umbilical vein endothelial cells (HUVECs) and observed the effects of dexmedetomidine on U937-HUVEC adhesion. Specific siRNA was designed to knock-down Connexin43 (Cx43) expression in U937 monocytes. Gö6976, GSK2795039, and NAC were used to inhibit PKC-α, NOX2, and ROS, respectively. Then, we detected whether dexmedetomidine could downregulate Cx43 expression and its downstream PKC-α/NOX2/ROS signaling pathway activation and ultimately result in the decrease of U937-HUVEC adhesion. The results showed that dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), could inhibit adhesion of molecule expression (VLA-4 and LFA-1) and U937-HUVEC adhesion. Simultaneously, it also attenuated Cx43 expression in U937 monocytes. With the downregulation of Cx43 expression, the activity of PKC-α and its related NOX2/ROS signaling pathway were reduced. Inhibiting PKC-α/NOX2/ROS signaling pathway with Gö6976, GSK2795039, and NAC, respectively, VLA-4, LFA-1 expression, and U937-HUVEC adhesion were all decreased. In summary, we concluded that dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), decreased Cx43 expression in U937 monocytes and PKC-α associated with carboxyl-terminal domain of Cx43 protein. With the downregulation of PKC-α, the NOX2/ROS signaling pathway was inhibited, resulting in the decrease of VLA-4 and LFA-1 expression. Ultimately, U937-HUVEC adhesion was reduced.

Highlights

The recruitment of circulating monocytes to inflamed tissues is one of the most important characters of acute and chronic inflammatory responses
The results showed that when U937 monocytes were exposed to LPS, U937-human umbilical vein endothelial cells (HUVECs) adhesion were increased significantly, which could be attenuated by dexmedetomidine (0.1 nM and 1 nM for 24 hours) application (Figure 1(a))
The ligands of VCAM-1 and ICAM-1 expressed in U937 monocytes, VLA-4, and LFA-1 were downregulated by dexmedetomidine (Figure 1(b))

Summary

Introduction

The recruitment of circulating monocytes to inflamed tissues is one of the most important characters of acute and chronic inflammatory responses. The migration of monocytes involves sequential molecular interactions with endothelial cells, known as the adhesion cascade, in which firm monocyte-endothelial adherence is the fundamental step [1, 2]. There are lots of risk factors that can increase monocyte-endothelial adherence, the most important one of which is just LPS, an outer membrane component of Gram-negative bacteria [1, 3]. LPS directly activates monocytes, resulting in its adherence to endothelial cells or the extracellular matrix [4]. Long-term supine position leads monocyte-endothelial adherence to become easier. Monocyte-endothelial adherence and its related inflammatory damage are more likely to occur in such critical patients

Methods

Results

Discussion

Conclusion