Acute lung injury (ALI) and respiratory distress can develop as a consequence of sepsis with pathogens such as Group A streptococcus (GAS) including S. pyogenes. In the pathogenesis of sepsis-associated ALI, plasma exudation and leukocyte accumulation in the lungs are central events, and endothelial barrier disruption brought on by degranulation of neutrophil-derived proteins is considered a causative factor. Heparin and heparin derivatives have been suggested as novel therapeutics in sepsis on the basis of their pleiotropic anti-inflammatory effects.
Here, we study wheter sevuparin, a heparinoid wihich lacks anticoagulant activity, affects neutrophil-induced lung plasma leakage.
A murine model of systemic inflammation evoked by heat-killed GAS and furthermore, we utilized human neutrophils and endothelial cell monolayers
We demonstrate that sevuparin inhibits hkGAS-induced endothelial barrier disruption by neutralizing the activity of neutrophil-derived proteins. By mass spectrometry of neutrophil secretion we identify candidate proteins, including serprocidins, S100 proteins and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity.
Collectively, our results corroborate the role of neutrophil-derived proteins in vascular hyperpermeability caused by Group A streptococci, and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation.