KFO 342 - P1: Procalcitonin as a Mediator of Sepsis-induced Endothelial Barrier Dysfunction

Basic data for this project

Description

Sepsis is a life-threatening immune reaction triggered by the invasion of (mostly bacterial) pathogens into the blood stream. Patients suffering from sepsis exhibit hypotension, tissue edema and impaired microcirculation leading to tissue hypoxia, organ dysfunction and high mortality. At the cellular level, sepsis induces endothelial dysfunction resulting in a loss of endothelial barrier integrity. Although preclinical investigations suggest promoting endothelial function during sepsis can lower sepsis complications, the underlying mechanisms are incompletely understood and no therapeutic tool is available to limit endothelial dysfunction and improve microcirculatory flow during sepsis. Procalcitonin is a 116 amino acid hormokine ubiquitously expressed by immune and parenchymal cells during sepsis. Procalcitonin’s plasma concentrations increase up to 100.000-fold during sepsis and correlate with sepsis severity and outcome. Hence, procalcitonin is a clinically well characterized biomarker for the diagnosis, treatment and prognosis of patients with sepsis but it is yet unknown whether and how procalcitonin itself functions in sepsis. Our previous studies and preliminary data show that procalcitonin itself is a mediator of endothelial dysfunction. Importantly, procalcitonin induces loss of endothelial barrier integrity by reducing endothelial surface levels of vascular endothelial-cadherin (VE-cadherin) resulting in tissue edema in vivo. Full length procalcitonin (PCT1-116) is cleaved by dipeptidyl peptidase IV (DPPIV) to PCT3-116 and our preliminary data show that cleavage of PCT1-116 by DPPIV triggers the barrier-disrupting activity.