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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.
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.
摘要：
背景：二肽基肽酶3（DPP3）是一种普遍存在的细胞溶质酶，在组织损伤后释放到血流中，能降解血管紧张素II.高浓度的循环DPP3(cDPP3)与脓毒症期间更差的结果相关。这项研究的目的是评估Procizumab（PCZ）的效果，在感染性休克的实验模型中，一种中和cDPP3的单克隆抗体。
方法：在本随机分组中，开放标签，对照研究,当平均动脉压（MAP）降至50mmHg以下时，将16只患有腹膜炎的麻醉和机械通气猪随机接受PCZ或标准治疗。用液体复苏，抗菌治疗,腹腔灌洗,一小时后开始去甲肾上腺素，以将MAP维持在65-75mmHg之间12小时。血液动力学变量，组织氧合指数，并收集器官衰竭和心肌损伤的测量值。使用同位素评估（99mtech白蛋白）评估器官血流。cDPP3活性，对肾素-血管紧张素系统和循环儿茶酚胺进行平衡分析.在血管和心肌样本上评估了白细胞介素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。
结果：PCZ治疗的动物的cDPP3水平降低，需要的去甲肾上腺素和液体比败血症对照动物少，器官灌注和局部血流量相似。PCZ处理的动物心肌损伤较少，和更高的PaO2/FiO2比率。PCZ与较低的循环儿茶酚胺水平相关；较高的循环血管紧张素II和较高的血管紧张素II受体1型心肌蛋白表达，心肌和桡动脉白细胞介素-6mRNA表达较低。
结论：在感染性休克的实验模型中，PCZ给药与液体和儿茶酚胺需求减少有关，减少心肌损伤和心血管炎症，以及保留的血管紧张素II信号。
方法：在本随机分组中，开放标签，对照研究,当平均动脉压（MAP）降至50mmHg以下时，将16只患有腹膜炎的麻醉和机械通气猪随机接受PCZ或标准治疗。用液体复苏，抗菌治疗,腹腔灌洗,一小时后开始去甲肾上腺素，以将MAP维持在65-75mmHg之间12小时。血液动力学变量，组织氧合指数，并收集器官衰竭和心肌损伤的测量值。使用同位素评估（99mtech白蛋白）评估器官血流。cDPP3活性，对肾素-血管紧张素系统和循环儿茶酚胺进行平衡分析.在血管和心肌样本上评估了白细胞介素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。
结果：PCZ治疗的动物的cDPP3水平降低，需要的去甲肾上腺素和液体比败血症对照动物少，器官灌注和局部血流量相似。PCZ处理的动物心肌损伤较少，和更高的PaO2/FiO2比率。PCZ与较低的循环儿茶酚胺水平相关；较高的循环血管紧张素II和较高的血管紧张素II受体1型心肌蛋白表达，心肌和桡动脉白细胞介素-6mRNA表达较低。
结论：在感染性休克的实验模型中，PCZ给药与液体和儿茶酚胺需求减少有关，减少心肌损伤和心血管炎症，以及保留的血管紧张素II信号。
