Vasculotide reduces pulmonary hyperpermeability in experimental pneumococcal pneumonia

Crit Care. 2017 Nov 13;21(1):274. doi: 10.1186/s13054-017-1851-6.


Background: Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality worldwide. Despite effective antimicrobial therapy, CAP can induce pulmonary endothelial hyperpermeability resulting in life-threatening lung failure due to an exaggerated host-pathogen interaction. Treatment of acute lung injury is mainly supportive because key elements of inflammation-induced barrier disruption remain undetermined. Angiopoietin-1 (Ang-1)-mediated Tie2 activation reduces, and the Ang-1 antagonist Ang-2 increases, inflammation and endothelial permeability in sepsis. Vasculotide (VT) is a polyethylene glycol-clustered Tie2-binding peptide that mimics the actions of Ang-1. The aim of our study was to experimentally test whether VT is capable of diminishing pneumonia-induced lung injury.

Methods: VT binding and phosphorylation of Tie2 were analyzed using tryptophan fluorescence spectroscopy and phospho-Tie-2 enzyme-linked immunosorbent assay. Human and murine lung endothelial cells were investigated by immunofluorescence staining and electric cell-substrate impedance sensing. Pulmonary hyperpermeability was quantified in VT-pretreated, isolated, perfused, and ventilated mouse lungs stimulated with the pneumococcal exotoxin pneumolysin (PLY). Furthermore, Streptococcus pneumoniae-infected mice were therapeutically treated with VT.

Results: VT showed dose-dependent binding and phosphorylation of Tie2. Pretreatment with VT protected lung endothelial cell monolayers from PLY-induced disruption. In isolated mouse lungs, VT decreased PLY-induced pulmonary permeability. Likewise, therapeutic treatment with VT of S. pneumoniae-infected mice significantly reduced pneumonia-induced hyperpermeability. However, effects by VT on the pulmonary or systemic inflammatory response were not observed.

Conclusions: VT promoted pulmonary endothelial stability and reduced lung permeability in different models of pneumococcal pneumonia. Thus, VT may provide a novel therapeutic perspective for reduction of permeability in pneumococcal pneumonia-induced lung injury.

Keywords: Acute lung injury; Angiopoietins; Pneumococcal pneumonia; Pneumolysin; Vasculotide.

MeSH terms

  • Animals
  • Capillary Permeability / drug effects*
  • Community-Acquired Infections / drug therapy
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Female
  • Lung / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / pharmacokinetics*
  • Peptide Fragments / therapeutic use
  • Pneumonia, Pneumococcal / drug therapy
  • Spectrometry, Fluorescence / methods
  • Statistics, Nonparametric
  • Streptococcus pneumoniae / metabolism
  • Streptococcus pneumoniae / pathogenicity


  • Peptide Fragments
  • Vasculotide