Fadel Fouad, André-Grégoire Gwennan, Gravez Basile, Bauvois Brigitte, Bouchet Sandrine, Sierra-Ramos Catalina, Polito Andrea, Mansart Arnaud, Alvarez de la Rosa Diego, Annane Djillali, Jaisser Frédéric
1INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France. 2Intensive Care Unit, Raymond Poincaré Hospital, Assistance Publique Hôpitaux de Paris (APHP), Garches, France. 3Intensive Care Unit, René Dubos Hospital, Pontoise, France. 4INSERM, UMRS 1173, Team 2, Versailles-Saint-Quentin-en-Yvelines University, Versailles, France. 5Assistance Publique Hôpitaux de Paris (APHP), Paris, France. 6Department of Physiology, Universidad de La Laguna, Santa Cruz de Tenerife, Spain. 7INSERM, Clinical Investigation Centre 1433, Vandoeuvre-lès-Nancy, France.
Crit Care Med. 2017 Sep;45(9):e954-e962. doi: 10.1097/CCM.0000000000002462.
Vascular mineralocorticoid receptors play a role in vascular tone and blood pressure regulation, might participate in the pathophysiology of circulatory failure during sepsis, and represent a potential therapeutic target in this disease. We aimed to study the effects of mineralocorticoids and the involvement of vascular mineralocorticoid receptors in murine endotoxic and human septic shock.
Experimental study.
Translational investigation including animal research and in vitro experiments using human vascular cells and plasma from septic patients.
Adult male C57Black 6 mice, adult patients with septic shock.
Mice were injected with lipopolysaccharide and/or aldosterone. Human endothelial and smooth muscle cells were treated with pro-inflammatory cytokines with or without aldosterone, nuclear factor-κB inhibitor BAY 11-7082, or plasma from septic patients.
Aldosterone improved 5-day survival, invasive arterial pressure, and in vivo and ex vivo arterial response to phenylephrine at 18 hours after induction of murine endotoxic shock. Both α1-adrenoceptor and mineralocorticoid receptor expressions studied in mouse aortas were down-regulated at 6 and 18 hours in endotoxemic mice and restored in aldosterone-treated mice. Furthermore, tumor necrosis factor-α decreased both mineralocorticoid receptor and α1-adrenoceptor expressions within 5 hours in human vascular cells in a nuclear factor-κB pathway-dependent manner. Mineralocorticoid receptor expression was also blunted in human cells treated with plasma from septic patients.
We found a beneficial effect of mineralocorticoids on survival, blood pressure, and vascular reactivity, associated with a restoration of α1-adrenoceptor expression in endotoxic shock. Furthermore, blunted vascular mineralocorticoid receptor expression might participate in hemodynamic failure during sepsis.
血管盐皮质激素受体在血管张力和血压调节中起作用，可能参与脓毒症期间循环衰竭的病理生理过程，并且是该疾病的一个潜在治疗靶点。我们旨在研究盐皮质激素的作用以及血管盐皮质激素受体在小鼠内毒素血症和人类脓毒性休克中的参与情况。
实验研究。
包括动物研究以及使用人类血管细胞和脓毒症患者血浆进行体外实验的转化研究。
成年雄性C57Black 6小鼠、成年脓毒性休克患者。
给小鼠注射脂多糖和/或醛固酮。用人促炎细胞因子联合或不联合醛固酮、核因子-κB抑制剂BAY 11-7082或脓毒症患者的血浆处理人内皮细胞和平滑肌细胞。
在诱导小鼠内毒素血症休克后18小时，醛固酮改善了5天生存率、有创动脉压以及体内和体外动脉对去氧肾上腺素的反应。在内毒素血症小鼠的主动脉中研究的α1-肾上腺素能受体和盐皮质激素受体表达在6小时和18小时时均下调，而在醛固酮治疗的小鼠中恢复。此外，肿瘤坏死因子-α在5小时内以核因子-κB途径依赖的方式降低了人类血管细胞中的盐皮质激素受体和α1-肾上腺素能受体表达。用脓毒症患者血浆处理的人类细胞中盐皮质激素受体表达也减弱。
我们发现盐皮质激素对生存率、血压和血管反应性有有益作用，这与内毒素血症休克中α1-肾上腺素能受体表达的恢复有关。此外，血管盐皮质激素受体表达减弱可能参与脓毒症期间的血流动力学衰竭。
