在实验性脓毒性休克中，普罗西单抗对循环二肽基肽酶3的抑制作用可减少儿茶酚胺暴露并减轻心肌损伤。

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

作者信息

Garcia Bruno, Ter Schiphorst Benoit, Santos Karine, Su Fuhong, Dewachter Laurence, Vasques-Nóvoa Francisco, Rocha-Oliveira Estela, Roncon-Albuquerque Roberto, Uba Theo, Hartmann Oliver, Picod Adrien, Azibani Feriel, Callebert Jacques, Goldman Serge, Annoni Filippo, Favory Raphaël, Vincent Jean-Louis, Creteur Jacques, Taccone Fabio Silvio, Mebazaa Alexandre, Herpain Antoine

机构信息

Experimental Laboratory of the Department of Intensive Care, Université Libre de Bruxelles (ULB), Brussels, Belgium.

Department of Intensive Care, Centre Hospitalier Universitaire de Lille, Lille, France.

出版信息

Intensive Care Med Exp. 2024 Jun 7;12(1):53. doi: 10.1186/s40635-024-00638-3.

DOI:10.1186/s40635-024-00638-3

PMID:38849640

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11161450/

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 (technetium 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 PaO/FiO 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.

摘要

背景

二肽基肽酶3（DPP3）是一种广泛存在于细胞溶质中的酶，在组织损伤后释放到血液中，可降解血管紧张素II。脓毒症期间，循环中高浓度的DPP3（cDPP3）与更差的预后相关。本研究旨在评估一种中和cDPP3的单克隆抗体——普罗珠单抗（PCZ）在脓毒性休克实验模型中的作用。

方法

在这项随机、开放标签、对照研究中，16只患有腹膜炎的麻醉且机械通气的猪在平均动脉压（MAP）降至50 mmHg以下时，被随机分配接受PCZ或标准治疗。1小时后开始进行液体复苏、抗菌治疗、腹腔灌洗和使用去甲肾上腺素，以将MAP维持在65 - 75 mmHg达12小时。收集血流动力学变量、组织氧合指数以及器官功能衰竭和心肌损伤的指标。使用同位素评估（锝标记白蛋白）来评估器官血流。测量cDPP3活性、肾素 - 血管紧张素系统的平衡分析以及循环儿茶酚胺。在血管和心肌样本上评估白细胞介素 - 6的组织mRNA表达以及肾上腺素能和血管紧张素受体的下调情况。

结果

与脓毒症对照动物相比，接受PCZ治疗的动物cDPP3水平降低，在类似的器官灌注和局部血流情况下，所需的去甲肾上腺素和液体更少。接受PCZ治疗的动物心肌损伤较轻，且氧合指数（PaO/FiO）更高。PCZ与较低的循环儿茶酚胺水平相关；与较高的循环血管紧张素II和较高的1型血管紧张素II受体心肌蛋白表达相关，并且与较低的心肌和桡动脉mRNA白细胞介素 - 6表达相关。