Extracorporeal Resuscitation with Carbon Monoxide Improves Renal Function by Targeting Inflammatory Pathways in Cardiac Arrest in Pigs.
Extracorporeal Resuscitation with Carbon Monoxide Improves Renal Function by Targeting Inflammatory Pathways in Cardiac Arrest in Pigs.
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DOI：
10.1152/ajprenal.00241.2019
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发表时间：
2019-09
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通讯作者：
J. Wollborn;B. Schlueter;C. Steiger;Cornelius Hermann;C. Wunder;Johannes Schmidt;P. Diel;L. Meinel;H. Buerkle;U. Goebel;M. Schick
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作者：
J. Wollborn;B. Schlueter;C. Steiger;Cornelius Hermann;C. Wunder;Johannes Schmidt;P. Diel;L. Meinel;H. Buerkle;U. Goebel;M. Schick
背景心脏骤停成功复苏后经常发生急性肾损伤等不良后果。体外生命支持越来越多地用于克服心脏骤停的高死亡率。一氧化碳（CO）是一种内源性气体递质，能够减轻肾损伤。在我们的研究中，我们假设在心脏骤停的猪模型中，体外复苏中加入CO会阻碍肾损伤的严重程度。方法建立猪低氧性心脏骤停模型。使用常规（CPR）、体外（E-CPR）或CO辅助体外（CO-E-CPR）方案复苏动物。使用膜控制释放系统施加CO。测量肾损伤的标志物并进行组织病理学分析。我们研究了涉及炎症以及凋亡性细胞死亡的肾脏途径。结果与Sham动物相比，CO处理后血清中性粒细胞明胶酶相关脂质运载蛋白（NGAL）无差异（Sham 71±7和CO-E-CPR 95±6 ng/ml），而CPR和E-CPR组NGAL增加（CPR 135±11和E-CPR 124±5 ng/ml; p<0.05）。CO应用后，组织病理学损伤的证据被废除。CO增加肾热休克蛋白70的表达并减少诱导型环氧合酶2（CPR 60±8; E-CPR 56±8; CO-E-CPR 31±3 μg/ml; p<0.05）。Caspase 3活性降低（CPR 1469±276; E-CPR 1670±225; CO-E-CPR 755±83 pg/ml; p<0.05）。此外，我们发现CO治疗后肾脏炎症信号减少。结论：我们的数据表明，在心脏骤停的猪模型中，体外CO治疗可改善肾功能。CO减少了促炎和促凋亡信号传导，表征了克服高死亡率的新型治疗选择的有益方面。
BACKGROUND Deleterious consequences like acute kidney injury frequently occur upon successful resuscitation from cardiac arrest. Extracorporeal life support is increasingly used to overcome high cardiac arrest mortality. Carbon monoxide (CO) is an endogenous gasotransmitter, capable of reducing renal injury. In our study, we hypothesize that addition of CO to extracorporeal resuscitation hampers severity of renal injury in a porcine model of cardiac arrest. METHODS Hypoxic cardiac arrest was induced in pigs. Animals were resuscitated using a conventional (CPR), an extracorporeal (E-CPR) or a CO-assisted extracorporeal (CO-E-CPR) protocol. CO was applied using a membrane-controlled releasing system. Markers of renal injury were measured and histopathological analyses were carried out. We investigated renal pathways involving inflammation as well as apoptotic cell death. RESULTS No differences in serum neutrophil gelatinase-associated lipocalin (NGAL) were detected after CO treatment compared to Sham animals (Sham 71±7 and CO-E-CPR 95±6 ng/ml), while NGAL was increased in CPR and E-CPR groups (CPR 135±11 and E-CPR 124±5 ng/ml; p<0.05). Evidence for histopathological damage was abrogated after CO application. CO increased renal heat-shock protein 70 expression and reduced inducible cyclooxygenase 2 (CPR 60±8; E-CPR 56±8; CO-E-CPR 31±3 µg/ml; p<0.05). Caspase 3 activity was decreased (CPR 1469±276; E-CPR 1670±225; CO-E-CPR 755±83 pg/ml; p<0.05). Furthermore, we found a reduction in renal inflammatory signaling upon CO treatment. CONCLUSION Our data demonstrates improved renal function by extracorporeal CO treatment in a porcine model of cardiac arrest. CO reduced pro-inflammatory and pro-apoptotic signaling, characterizing beneficial aspects of a novel treatment option to overcome high mortality.