Targeting Procalcitonin Protects Vascular Barrier Integrity

Regulation and Dysregulation of Endothelial Permeability during Systemic Inflammation

“…Enzymatic cleavage is facilitated by dipeptidyl peptidase 4 (DPP4) via N-terminal removal of the two amino acids alanine and proline [ 178 ]. Procalcitonin exerts actions on the CGRP receptor, which is a heterodimer formed by CRLR/RAMP1 [ 173 , 179 , 180 ]. Interestingly, elevated procalcitonin levels after major surgery are also indicative for organ dysfunction [ 181 , 182 ].…”

“…Interestingly, elevated procalcitonin levels after major surgery are also indicative for organ dysfunction [ 181 , 182 ]. Recently, data from our research group showed that elevated procalcitonin levels after cardiopulmonary bypass surgery identifies patients with signs of postoperative capillary leakage and increased requirements for fluids and vasopressors, and suggest an impairment of microvascular integrity [ 180 ]. We identified that procalcitonin levels of 10 ng/ml, typically observed in septic patients [ 183 ], induce severe pulmonary edema formation in healthy wild type mice.…”

“…Further, procalcitonin deficiency increased survival during murine peritoneal sepsis [ 173 ]. We and others have shown that blocking procalcitonin receptor by olcegepant, which is a CRLR/RAMP1 antagonist currently used in migraine treatment research [ 184 ], is a feasible means to ameliorate procalcitonin’s edema-inducing effects, further protects the vascular barrier function and improves murine survival in polymicrobial sepsis [ 173 , 180 ]. However, recent evidence from the evaluation of olcegepant in porcine sepsis suggests that novel pharmacological substances are needed before targeting the procalcitonin/CRLR signaling axis can be moved towards a clinical evaluation [ 185 ].…”

“…Interestingly, prior studies have also shown that DPP4 inactivation preserves endothelial function and increases murine survival in endotoxic shock [ 186 , 187 ]. In a prospective clinical pilot study of cardiac surgery patients, we shed light on a potential translational relevance as sitagliptin intake prior to surgery was associated with ameliorated postoperative capillary leakage [ 180 ]. To date, gliptins have only been approved for oral intake, while septic patients often exhibit gastroparesis and altered bioavailability of orally delivered drugs.…”

ARDS in the time of corona: context and perspective

“…1 ). In a more translational example, Brabenec et al ( 64 ) recently identified procalcitonin as an endothelial barrier-disruptive mediator. As procalcitonin requires activation by dipeptidyl-peptidase 4 (DPP4), DPP4 inhibitors such as the clinically approved drug sitagliptin are a means to interfere with this pathway.…”