Therapeutic interventions in shock:Responses of the (microvascular) endothelium

Shock is associated with a high morbidity and mortality, and prompt recognition and medical management are essential to correct the cause of shock and stabilize the associated physiological disturbances. Effective therapeutic strategies for the treatment of shock patients remain a challenging conundrum in clinical care. In this thesis, we investigated potential therapeutic strategies for the treatment of shock associated changes in microvascular endothelial behavior in hemorrhage and sepsis. Our aims were to understand the role of microvascular flow alterations in regulating endothelial behavior and test the effects of different therapeutic interventions on the inflammatory activation status of microvascular endothelial cells created by flow alterations and cytokines both in vitro and in vivo. Shock is associated with a decrease and loss of intravascular blood flow. In our in vitro study, the abrupt reflow related enhancement of cytokine-induced endothelial pro-inflammatory activation supports the concept that sudden regain of perfusion during resuscitation has an aggravating effect on endothelial pro-inflammatory activation, which may play a significant role in vascular dysfunction and consequent organ injury after recovery from shock. Furthermore, the in vivo pharmacological interventions in hemorrhagic shock and resuscitation model imply the potential of histone deacetylase inhibition and NF-κB inhibition in the treatment of this condition. In addition, using SAINT-O-Somes as carriers of dexamethasone to target to vascular adhesion molecule (VCAM-1) expressed on the surface of endothelial cells, we demonstrated the specific delivery of the carriers in inflamed endothelial cells in sepsis, the therapeutic impact of which needs further investigation