Hagimont Eugénie, Lourenco-Rodrigues Marc-Damien, Chousterman Benjamin-Glenn, Yen-Potin Frances, Durand Manon, Kimmoun Antoine
Inserm U1116, DCAC, Université de Lorraine, Nancy, France.
APHP, CHU Lariboisière, Département d'anesthésiologie et Réanimation, Inserm, MASCOT Paris, Université Paris Cité, Paris, France.
Intensive Care Med Exp. 2024 Dec 18;12(1):118. doi: 10.1186/s40635-024-00705-9.
Recent findings suggest that β3-adrenergic receptors (β3-AR) could play a role in the hemodynamic regulation, but their function in septic shock remains unclear. This study investigates the modulation of β3-AR in an experimental murine model of resuscitated septic shock on in vivo hemodynamic, ex vivo vasoreactivity, inflammation and survival.
Wild-type mice were used, undergoing cecal ligation and puncture (CLP) to induce septic shock, with SHAM as controls. Mice were treated with β3-AR agonist or antagonist three hours post-CLP, followed by resuscitation with fluids and antibiotics. Hemodynamic parameters were measured at 18 h following the surgery, and the expression of β-ARs in heart and aorta was assessed via immunostaining and western blot. Vascular reactivity was studied using myography, and inflammatory markers were analyzed through PCR and western blots. A 5-day survival study was conducted, documenting clinical severity scores and survival rates.
β3-AR was expressed in both endothelial and myocardial cells in healthy and septic mice. During septic shock model, β3-AR density on endothelial cells increased post-CLP, while β1- and β2-AR decreased or remained constant. β3-AR antagonist treatment improved hemodynamic parameters, increasing mean arterial pressure and cardiac index, unlike the agonist. Vascular reactivity to phenylephrine was enhanced in aortic rings from both β3-AR agonist and antagonist-treated mice. However, no significant differences in inducible NO synthase expression were observed among treated groups. Despite improved hemodynamic parameters with β3-AR antagonist treatment, survival rates in treated groups remained similar to CLP group.
In an experimental murine model of resuscitated septic shock, β3-AR is resistant to desensitization and its inhibition improves cardiac and vascular function without affecting the short-term survival.
最近的研究结果表明，β3-肾上腺素能受体（β3-AR）可能在血流动力学调节中发挥作用，但其在感染性休克中的功能仍不清楚。本研究在复苏后的感染性休克实验小鼠模型中，研究β3-AR对体内血流动力学、体外血管反应性、炎症和生存的调节作用。
使用野生型小鼠，通过盲肠结扎和穿刺（CLP）诱导感染性休克，以假手术组作为对照。CLP术后3小时，小鼠接受β3-AR激动剂或拮抗剂治疗，随后进行液体复苏和抗生素治疗。术后18小时测量血流动力学参数，并通过免疫染色和蛋白质印迹法评估心脏和主动脉中β-AR的表达。使用血管张力测定法研究血管反应性，并通过聚合酶链反应和蛋白质印迹法分析炎症标志物。进行为期5天的生存研究，记录临床严重程度评分和生存率。
β3-AR在健康小鼠和感染小鼠的内皮细胞和心肌细胞中均有表达。在感染性休克模型中，CLP术后内皮细胞上的β3-AR密度增加，而β1-AR和β2-AR减少或保持不变。与激动剂不同，β3-AR拮抗剂治疗改善了血流动力学参数，增加了平均动脉压和心脏指数。β3-AR激动剂和拮抗剂治疗的小鼠主动脉环对去氧肾上腺素的血管反应性均增强。然而，各治疗组之间诱导型一氧化氮合酶表达未见显著差异。尽管β3-AR拮抗剂治疗改善了血流动力学参数，但治疗组的生存率与CLP组相似。
在复苏后的感染性休克实验小鼠模型中，β3-AR对脱敏具有抗性，其抑制可改善心脏和血管功能，而不影响短期生存。
