Neferine Protects Endothelial Glycocalyx via Mitochondrial ROS in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome.

Xiang-Yong Liu,Xiao-Hong Ma,Jian-Kui Li,Hai-Xiao Xu,Jun-Hong Lü,Xiao-Zhi Wang,Dong Zhang,Li-Na Huang

doi:10.3389/fphys.2018.00102

Abstract

Damage to the endothelial glycocalyx is a critical factor in increased pulmonary vascular permeability, which is the basic pathological feature of acute respiratory distress syndrome (ARDS). Neferine (Nef), a bisbenzylisoquinoline alkaloid isolated from green seed embryos of Nelumbo nucifera Gaertn, has extensive pharmacological activity. In this study, we showed that Nef reduced lung-capillary permeability, down-regulated the production of cytokines (IL-1β, IL-6, TNF-α, and IL-10) and inhibited the activation of the NF-κB signaling pathway in mice with lipopolysaccharide (LPS)-induced ARDS. Further analysis indicated that Nef provided protection against endothelial glycocalyx degradation in LPS-induced ARDS mice (in vivo) and in LPS-stimulated human umbilical vein endothelial cells (in vitro). The glycocalyx-protective effect of Nef may be initiated by suppressing the production of mitochondrial ROS (mtROS) and decreasing oxidative damage. Nef was also found to promote glycocalyx restoration by accelerating the removal of mtROS in endothelial cells in LPS-induced ARDS. These results suggested the potential of Nef as a therapeutic agent for ARDS associated with Gram-negative bacterial infections and elucidated the mechanisms underlying the protection and restoration of the endothelial glycocalyx.

Highlights

Acute respiratory distress syndrome (ARDS), a significant source of morbidity and mortality in critically ill patients, is characterized by the abrupt onset of clinically significant hypoxemia with the presence of diffuse pulmonary infiltrates
We investigated the effect of Nef on the pulmonary vascular permeability in LPS-induced ARDS
The endothelial glycocalyx serves as the primary physical barrier and interface between the blood and the vessel wall, which is damaged in ARDS

Summary

Introduction

Acute respiratory distress syndrome (ARDS), a significant source of morbidity and mortality in critically ill patients, is characterized by the abrupt onset of clinically significant hypoxemia with the presence of diffuse pulmonary infiltrates. The endothelial glycocalyx is a network of membrane-bound proteoglycans and glycosaminoglycans that covers the healthy vascular endothelium (Yang and Schmidt, 2013) It mostly consists of a core protein and side chains. The endothelial glycocalyx serves as the primary physical barrier and interface between the blood and the vessel wall and plays a crucial role in regulating vascular endothelial permeability (Salmon and Satchell, 2012; Yang and Schmidt, 2013; Mehta et al, 2014; Chelazzi et al, 2015) It plays an important role in the mechanosensing that mediates the NO production that protects endothelial cells from blood-flowinduced shear stress. Damage to the glycocalyx can have many pathophysiological consequences, such as increased vascular permeability, edema formation, increased adhesion of circulating inflammatory cells to the endothelium, accelerated inflammatory process, activation of the coagulation cascade, and platelet hyperaggregation. (Reitsma et al, 2007; Yang and Schmidt, 2013; Kolárová et al, 2014; Chelazzi et al, 2015; Yen et al, 2015; Schött et al, 2016; Sieve et al, 2018)

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