2. Academic Validation
  3. Inhibition of circulating dipeptidyl-peptidase 3 by procizumab in experimental septic shock reduces catecholamine exposure and myocardial injury

Inhibition of circulating dipeptidyl-peptidase 3 by procizumab in experimental septic shock reduces catecholamine exposure and myocardial injury

  • Intensive Care Med Exp. 2024 Jun 7;12(1):53. doi: 10.1186/s40635-024-00638-3.
Bruno Garcia 1 2,  Benoit Ter Schiphorst 3 4,  Karine Santos 5,  Fuhong Su 3,  Laurence Dewachter 6,  Francisco Vasques-Nóvoa 7,  Estela Rocha-Oliveira 7,  Roberto Roncon-Albuquerque Jr 7,  Theo Uba 5,  Oliver Hartmann 5,  Adrien Picod 8,  Feriel Azibani 8,  Jacques Callebert 8 9,  Serge Goldman 10,  Filippo Annoni 3 11,  Raphaël Favory 4,  Jean-Louis Vincent 3 11,  Jacques Creteur 3 11,  Fabio Silvio Taccone 3 11,  Alexandre Mebazaa 8 12,  Antoine Herpain 3 13
Affiliations

Affiliations

  • 1 Experimental Laboratory of the Department of Intensive Care, Université Libre de Bruxelles (ULB), Brussels, Belgium. br.garcia@icloud.com.
  • 2 Department of Intensive Care, Centre Hospitalier Universitaire de Lille, Lille, France. br.garcia@icloud.com.
  • 3 Experimental Laboratory of the Department of Intensive Care, Université Libre de Bruxelles (ULB), Brussels, Belgium.
  • 4 Department of Intensive Care, Centre Hospitalier Universitaire de Lille, Lille, France.
  • 5 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany.
  • 6 Laboratory of Physiology and Pharmacology, Université Libre de Bruxelles (ULB), Brussels, Belgium.
  • 7 Cardiovascular R&D Center, Faculty of Medicine, University of Porto, Porto, Portugal.
  • 8 Université Paris Cité, UMR-S 942, INSERM, MASCOT, Paris, France.
  • 9 Department of Biochemistry, Assistance Publique Hôpitaux de Paris, Hôpital Lariboisière, Paris, France.
  • 10 Department of Nuclear Medicine, Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium.
  • 11 Department of Intensive Care, Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium.
  • 12 Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis-Lariboisière, AP-HP, Paris, France.
  • 13 Department of Intensive Care, Saint-Pierre University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium.
PMID: 38849640 DOI: 10.1186/s40635-024-00638-3
Abstract

Background: Dipeptidyl Peptidase 3 (DPP3) is a ubiquitous cytosolic Enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock.

Methods: In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65-75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin-angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples.

Results: PCZ-treated Animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control Animals for similar organ perfusion and regional blood flow. PCZ-treated Animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating Catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression.

Conclusions: In an experimental model of septic shock, PCZ administration was associated with reduced fluid and Catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling.

Keywords

Angiotensin II; Dipeptidyl peptidase 3; Renin–angiotensin system; Sepsis; Shock; Vasopressors.

Figures
Products