Therapeutic potential of plasma to protect the endothelial barrier in sepsis

The general aim of this thesis is to investigate whether plasma, or specific factors within plasma, as initial fluid resuscitation, can reduce pathological endothelial permeability and organ injury during sepsis. To achieve this, in vitro permeability assays, in vivo sepsis models, and a human volunteer endotoxemia model were used.
First, we made a comprehensive review of the potential benefits and risks associated with the use of plasma and plasma-derived proteins as a resuscitation fluid in shock. Using a rat model of pneumosepsis, the effects of various plasma products compared to the same volume of crystalloids on endothelial and organ injury were examined. Moreover, we investigated whether found potential benefits of plasma resuscitation were attributable to the type of fluid administered or to differences in resuscitation volume, by comparing plasma with varying volumes of crystalloids.
To evaluate the translational relevance of preclinical findings, a controlled human volunteer endotoxemia model was conducted. First, the impact of plasma versus crystalloid infusion on markers of endothelial injury, systemic inflammation, and coagulation were analyzed. Secondly, we investigated the effects of plasma compared to crystalloid resuscitation on the macro- and microcirculation.
The potential protective effects of plasma may result from the product as a whole or from specific repair factors. In this thesis, we investigated the effects of heparan sulfate on endothelial and organ injury in a rat pneumosepsis model. Finally, we explored the role of sphingosine-1-phosphate (S1P) in regulating endothelial barrier function during shock, using in vitro permeability assays.