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

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.

Dexmedetomidine Attenuates Monocyte-Endothelial Adherence via Inhibiting Connexin43 on Vascular Endothelial Cells.

Current studies have identified the multifaceted protective functions of dexmedetomidine on multiple organs. For the first time, we clarify effects of dexmedetomidine on monocyte-endothelial adherence and whether its underlying mechanism is relative to connexin43 (Cx43), a key factor regulating monocyte-endothelial adherence. U937 monocytes and human umbilical vein endothelial cells (HUVECs) were used to explore monocyte-endothelial adherence. Two special siRNAs were designed to knock down Cx43 expression on HUVECs. U937-HUVEC adhesion, adhesion-related molecules, and the activation of the MAPK (p-ERK1/2, p-p38, and p-JNK1/2) signaling pathway were detected. Dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), was given as pretreatments to HUVECs. Its effects on Cx43 and U937-HUVEC adhesion were also investigated. The results show that inhibiting Cx43 on HUVECs could attenuate the contents of MCP-1, soluble ICAM-1 (sICAM-1), soluble VCAM-1 (sVCAM-1), and the nonprocessed variants of the adhesion molecules ICAM-1 and VCAM-1 and ultimately result in U937-HUVEC adhesion decrease. Meanwhile, the activation of MAPKs was also inhibited. U0126 (inhibiting p-ERK1/2) and SB202190 (inhibiting p38) decreased the contents of MCP-1, sICAM-1, and sVCAM-1, but SP600125 (inhibiting p-JNK1/2) had none of these effects. ICAM-1 and VCAM-1 could be regulated in a similar way. Dexmedetomidine pretreatment inhibited Cx43 on HUVECs, the activation of MAPKs, and U937-HUVEC adhesion. Therefore, we conclude that dexmedetomidine attenuates U937-HUVEC adhesion via inhibiting Cx43 on HUVECs modulating the activation of MAPK signaling pathways.

Randomized Trial of an Improved Drainage Strategy Versus Routine Chest Tube After Lung Wedge Resection.

BACKGROUND: Patients undergoing thoracic lung wedge resection could benefit from tubeless strategies. However, postoperative pneumothorax is a primary limiting factor for such strategies. Accordingly, we evaluated the safety and efficacy of the prophylactic use of an air-extraction catheter as an improved drainage strategy and compared the findings with those for chest tube drainage in patients undergoing thoracic wedge resection. METHODS: Patients undergoing thoracic wedge resection between August 2017 and October 2018 were enrolled in this single-center, randomized, open-label, noninferiority trial. Patients who received an improved drainage strategy involving the use of a prophylactic air-extraction catheter were randomized to the intervention group, whereas those who underwent routine chest tube drainage were assigned to the control group. Analysis was based on the per-protocol population. The primary outcome was the incidence of pneumothorax on postoperative day 1. Secondary outcomes included patient recovery and related complications, including pleural effusion, lung infection, numeric rating scale score for pain, postoperative chest tube or catheter removal, postoperative hospitalization, and chest tube reinsertion. RESULTS: A total of 96 patients were randomized. Baseline demographic and clinical characteristics were similar between groups. The incidence of pneumothorax in the intervention and control groups was 10.0% and 9.1%, respectively (noninferiority, P = 1.00). In addition, there were no significant between-group differences in secondary outcomes. A significantly lower pain score was observed in the intervention group (P = .001). CONCLUSIONS: The improved drainage strategy is not inferior to standard chest tube drainage after thoracic wedge resection and should be popularized.