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

PLoS One. 2021 Apr 30;16(4):e0250327. doi: 10.1371/journal.pone.0250327. eCollection 2021.


Methods: Sepsis 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.

Results: In 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.

Conclusions: HMW-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Capillary Permeability / drug effects
  • Cell Movement / drug effects
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / immunology
  • Endothelial Cells / microbiology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / microbiology
  • Female
  • Gene Deletion
  • Glycocalyx / immunology
  • Glycocalyx / metabolism
  • Hyaluronic Acid / pharmacology*
  • Lung / drug effects
  • Lung / immunology
  • Lung / microbiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neutrophils / drug effects*
  • Neutrophils / immunology
  • Neutrophils / microbiology
  • Primary Cell Culture
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas Infections / immunology
  • Pseudomonas Infections / microbiology
  • Pseudomonas Infections / mortality
  • Pseudomonas aeruginosa / growth & development
  • Pseudomonas aeruginosa / pathogenicity
  • Sepsis / drug therapy*
  • Sepsis / immunology
  • Sepsis / microbiology
  • Sepsis / mortality
  • Smoke Inhalation Injury / drug therapy*
  • Smoke Inhalation Injury / immunology
  • Smoke Inhalation Injury / microbiology
  • Smoke Inhalation Injury / mortality
  • Survival Analysis
  • Syndecan-1 / deficiency
  • Syndecan-1 / genetics*
  • Syndecan-1 / immunology
  • Water / metabolism


  • Anti-Inflammatory Agents
  • Sdc1 protein, mouse
  • Syndecan-1
  • Water
  • Hyaluronic Acid