High molecular weight sodium hyaluronate improves survival of syndecan-1-deficient septic mice by inhibiting neutrophil migration.

Tuvshintugs Baljinnyam,Christina Nelson,Enkhtuya Radnaa,Jae-Woo Lee,Clark R Andersen,Perenlei Enkhbaatar,Donald S Prough,Vsevolod Popov,Yosuke Niimi,Casey M Ouellette,Mária A Deli

doi:10.1371/journal.pone.0250327

Abstract

We investigated the role of endothelial glycocalyx and its component syndecan-1 protein in the pathophysiology of sepsis-induced vascular hyper-permeability and examined the therapeutic effects of high-molecular-weight sodium hyaluronate (HMW-SH).MethodsSepsis was induced by cotton smoke inhalation followed by intranasal administration of Pseudomonas aeruginosa in female (> 6 months) Balb/c and syndecan-1 knockout mice. Survival of mice, lung capillary endothelial glycocalyx integrity, lung water content, and vascular hyper-permeability were determined with or without HMW-SH treatment in these mice. Effects of HMW-SH on endothelial permeability and neutrophil migration were tested in in vitro setting.ResultsIn septic wildtype mice, we found a severely damaged pulmonary microvascular endothelial glycocalyx and elevated levels of shed syndecan-1 in the circulation. These changes were associated with significantly increased pulmonary vascular permeability. In septic syndecan-1 knockout mice, extravascular lung water content was higher, and early death was observed. The administration of HMW-SH significantly reduced mortality and lung water content in septic syndecan-1 knockout mice, but not in septic wildtype mice. In in vitro setting, HMW-SH inhibited neutrophil migration and reduced cultured endothelial cell permeability increases. However, these effects were reversed by the addition of recombinant syndecan-1 ectodomain.ConclusionsHMW-SH reduced lung tissue damage and mortality in the absence of syndecan-1 protein, possibly by reducing vascular hyper-permeability and neutrophil migration. Our results further suggest that increased shed syndecan-1 protein levels are linked with the inefficiency of HMW-SH in septic wildtype mice.

Highlights

The most common cause of death in the intensive care unit (ICU) is sepsis, a syndrome whose outcome is determined by the interaction of pathogens with the host immune system [1]
We found a severely damaged pulmonary microvascular endothelial glycocalyx and elevated levels of shed syndecan-1 in the circulation
high-molecular-weight sodium hyaluronate (HMW-Sodium hyaluronate (SH)) inhibited neutrophil migration and reduced cultured endothelial cell permeability increases

Summary

Introduction

The most common cause of death in the intensive care unit (ICU) is sepsis, a syndrome whose outcome is determined by the interaction of pathogens with the host immune system [1]. In contrast to glycosaminoglycans (GAG), hyaluronan (hyaluronic acid) does not bind to proteoglycans, but instead interacts with cellular membrane CD44 glycoprotein; it is not sulfated and uncharged It can complex with other sulfated GAGs, enabling seclusion of water and stabilizing the gel-like structure of the glycocalyx [6]. The EGL interacts with a variety of enzymes, including endothelial nitric oxide synthase, angiotensinconverting enzymes, anti-thrombin III, apolipoprotein, and chemokines. It is involved in homeostasis, adherence of leukocyte and platelets, and transduction of shear stress signaling to the endothelium [7,8,9,10]. EGL is recognized as a critical player of the microvascular endothelial barrier function [11]

Objectives

Methods

Results

Conclusion