Vasculotide Reduces Pulmonary Permeability in Streptococcus pneumonia Infected and Mechanically Ventilated Mice

Introduction Community acquired pneumonia (CAP), commonly caused by Streptococcus pneumonia (S. pn.), is a significant cause of mortality worldwide. Despite adequate antibiotic treatment, pneumococcal pneumonia is able to provoke pulmonary endothelial hyperpermeability leading to potentially lethal lung edema and acute-respiratory distress syndrome (ARDS). This condition often requires mechanical ventilation (MV) causing additional damage to the lung (Ventilator-induced lung injury; VILI). Angiopoietin-1 mediated Tie2-receptor activation stabilizes the endothelial barrier and reduces vascular hyperpermeability. The PEGylated (polyethylene glycol) Tie2-agonist Vasculotide (VT) mimics Angiopietin-1 effects. Moreover, we have recently shown that VT reduces pulmonary hyperpermeability in murine pneumococcal pneumonia. The aim of our study was to investigate whether VT could ameliorate lung injury in S. pn. infected and mechanically ventilated mice.
Methods Mice were infected intranasally with S. pn. or received an equal amount of phosphate buffered saline. After 22 h they were treated either with or without Ampicillin ± VT. At 24 h post infection the mice were subjected to six hours of MV with a second dose of VT at 28.5 h post infection. Afterwards pulmonary hyperpermeability, immune cell response and bacterial load were quantified. Additionally, histological analysis was performed to evaluate pathomorphological lung changes due to pneumonia and VILI.
Results Ampicillin significantly reduced systemic cytokine levels and bacteremia without influencing endothelial permeability in ventilated and S. pn. infected mice. VT did not alter local or systemic immune responses or bacterial burden. Interestingly, combination treatment with Ampicillin and VT significantly reduced pulmonary hyperpermeability, histological lung damage and edema formation in S. pn. infected and mechanically ventilated mice compared to mere antibiotic therapy.
Conclusion Our results suggest that adjunctive therapy with VT may reduce ventilator induced lung injury in severe pneumococcal pneumonia.