Serum developmental endothelial locus-1 is associated with severity of sepsis in animals and humans

Won-Young Kim,Hyun Jin Ryu,Yan Fu,Sang-Bum Hong,Yun Young Park,Chae-Man Lim,Gyu Rak Chon,Younsuck Koh,Dong-Young Kim,Jin Won Huh,Eun Young Choi,Seung-Hwan Lee

doi:10.1038/s41598-019-49564-5

Abstract

Disruption of the endothelial glycocalyx has a prominent role in the pathophysiology of sepsis. Developmental endothelial locus-1 (Del-1) is an endothelial-derived anti-inflammatory factor. We hypothesized that degradation of the endothelial glycocalyx during sepsis may increase serum Del-1. A mouse model of sepsis was created using cecal ligation and puncture. In septic mice, the endothelial glycocalyx was nearly completely degraded, with less formation of Del-1 in the endothelium and extracellular matrix than in control mice. Serum Del-1 levels were significantly increased in the septic mice with increasing severity of sepsis. Serum Del-1 levels were also measured in 84 patients with sepsis and septic shock and in 20 control subjects. The median serum Del-1 level in patients with sepsis was significantly higher than that in healthy controls. The high Del-1 group had higher illness severity scores and contained more patients with organ dysfunction than the low Del-1 group. The 90-day mortality rate was significantly higher in the high Del-1 group than in the low Del-1 group. Multivariate analysis indicated a tendency for a high serum Del-1 level to be associated with a higher mortality risk. Increased serum Del-1 may be a novel diagnostic biomarker of sepsis and an indicator of disease severity.

Highlights

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection[1]
We investigated the ability of Developmental endothelial locus-1 (Del-1) to interact with heparan sulfate and syndecan-1, which is a major heparan sulfate proteoglycan constituting endothelial glycocalyx
This increased Del-1 levels significantly in the supernatant compared to control cells (Fig. 1D). These findings suggest that Del-1 is linked with the endothelium

Summary

Introduction

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection[1]. Hypoxia in the tissues produces large quantities of reactive oxygen and nitrogen species[4] These effects lead to endothelial dysfunction, refractory vasodilation, and disseminated intravascular coagulation (DIC). Developmental endothelial locus-1 (Del-1) is an endogenous inhibitor of endothelial adhesion of leukocytes. It antagonizes the interaction between lymphocyte function antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-18 as well as the binding of macrophage (Mac)-1 with complement fragment iC3b9. Del-1 may be an important homeostatic factor for preventing an inflammatory response in the endothelium and subsequent endothelial dysfunction[12]. Given that Del-1 is deposited in the endothelium and extracellular matrix[13] and that degradation of the endothelial glycocalyx is common in the course of sepsis[3,4], we www.nature.com/scientificreports/. To assess expression of serum Del-1 over time in both models, serum Del-1 levels were measured in mice that underwent cecal ligation and puncture (CLP) and in mice with lipopolysaccharide (LPS)-induced pneumonia

Methods

Results

Conclusion