Wilson Joel, Higgins David, Hutting Haley, Serkova Natalie, Baird Christine, Khailova Ludmila, Queensland Kelly, Vu Tran Zung, Weitzel Lindsay, Wischmeyer Paul E
Crit Care. 2013 Sep 10;17(5):R195. doi: 10.1186/cc12889.
Pharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis.
Sprague-Dawley rats receiving either repeated doses (30 minutes pre-CLP and every 8 hours for 24 hours postoperatively) of propranolol or control (normal saline), underwent CLP and were monitored for survival. Additionally, lung and blood samples were collected at 6 and 24 hours for analysis. Animals also underwent monitoring to evaluate global hemodynamics.
Seven days following CLP, propranolol improved survival versus control (P < 0.01). Heart rates in the propranolol-treated rats were approximately 23% lower than control rats (P < 0.05) over the first 24 hours, but the mean arterial blood pressure was not different between groups. Metabolic analysis of lung tissue demonstrated an increase in lung ATP/ADP ratio and NAD+ content and a decreased ratio of polyunsaturated fatty acids to monounsaturated fatty acids (PUFA/MUFA). Cytokine analysis of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) demonstrated decreased expression of TNF-alpha in both lung and plasma at 24 hours post CLP induced sepsis. Finally, propranolol led to a significant increase in lung hemeoxygenase-1 expression, a key cellular protective heat shock protein (HSP) in the lung. Other lung HSP expression was unchanged.
These results suggest that propranolol treatment may decrease mortality during sepsis potentially via a combination of improving metabolism, suppressing aspects of the inflammatory response and enhancing tissue protection.
阻断β-肾上腺素能受体的药物已被证明与改善烧伤预后有关。据推测，导致高代谢状态的损伤，如脓毒症休克，可能也会从β受体阻滞剂治疗中获益；然而，实验模型中的预后数据却相互矛盾。因此，我们在大鼠盲肠结扎穿孔（CLP）脓毒症模型中研究了普萘洛尔进行β受体阻滞对生存率、血流动力学、肺热休克蛋白（HSP）表达、代谢及炎症标志物的影响。
将Sprague-Dawley大鼠分为两组，一组在CLP前30分钟及术后24小时内每8小时重复给予普萘洛尔，另一组给予对照（生理盐水），然后进行CLP，并监测其生存率。此外，在6小时和24小时采集肺和血液样本进行分析。同时对动物进行监测以评估整体血流动力学。
CLP后7天，与对照组相比，普萘洛尔提高了生存率（P < 0.01）。在最初的24小时内，普萘洛尔治疗组大鼠的心率比对照组大鼠低约23%（P < 0.05），但两组间平均动脉血压无差异。肺组织代谢分析显示肺ATP/ADP比值和NAD+含量增加，多不饱和脂肪酸与单不饱和脂肪酸的比值（PUFA/MUFA）降低。对炎症细胞因子肿瘤坏死因子α（TNF-α）的细胞因子分析表明，在CLP诱导的脓毒症后24小时，肺和血浆中TNF-α的表达均降低。最后，普萘洛尔导致肺血红素加氧酶-1表达显著增加，这是肺中一种关键的细胞保护性热休克蛋白（HSP）。其他肺HSP表达未改变。
这些结果表明，普萘洛尔治疗可能通过改善代谢、抑制炎症反应的某些方面以及增强组织保护的综合作用降低脓毒症期间的死亡率。
