Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling.
Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling.
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DOI：
10.1186/1742-2094-6-30
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发表时间：
2009-10-22
影响因子：
9.3
通讯作者：
Wigginton JG
中科院分区：
文献类型：
--
作者：
Gatson JW;Maass DL;Simpkins JW;Idris AH;Minei JP;Wigginton JG
严重烧伤患者经历多种循环促炎细胞因子的快速升高，其水平与损伤严重程度和结果相关。这些细胞因子在动物模型中的积累已被观察到在远程器官，但数据缺乏烧伤后早期脑细胞因子水平，雌二醇对这些水平的影响。利用实验动物模型，我们研究了全层Ⅲ度烧伤对脑TNF-α、IL-1β和IL-6水平的急性影响，以及急性雌激素治疗对这些水平的保护作用。此外，通过测量安慰剂和雌激素治疗组中磷酸-ERK、磷酸-Akt、活性半胱天冬酶-3和PARP裂解的水平，研究了雌激素对严重烧伤后脑中炎症和凋亡事件的调节的急性给药。在这项研究中，149只成年Sprague-Dawley雄性大鼠接受了3度40%总体表面积（TBSA）烧伤。烧伤后15分钟，动物接受皮下注射安慰剂（n = 72）或17 β-雌二醇（n = 72）。在损伤后0.5、1、2、4、6、8、12、18和24小时从对照组（n = 5）、安慰剂组（n = 8/时间点）和雌激素治疗组（n = 8/时间点）动物中收获脑。采用ELISA方法测定脑细胞因子水平。此外，我们使用蛋白质印迹分析评估了24小时时间点的磷酸化ERK、磷酸化Akt、活性半胱天冬酶-3的水平和裂解的PARP的水平。在烧伤大鼠中，与安慰剂组相比，17 β-雌二醇显著降低了脑组织TNF-α（~25%）、IL-1β（~60%）和IL-6（~90%）的水平。此外，我们确定在雌激素处理的大鼠中，在24小时时间点磷酸化ERK（p < 0.01）和Akt（p < 0.05）的水平增加，并且17 β-雌二醇阻断半胱天冬酶-3的活化（p < 0.01）和随后的PARP裂解（p < 0.05）。严重烧伤后，雌激素减少脑炎症和细胞凋亡的激活，表现为磷酸化Akt水平的增加和caspase-3激活和PARP裂解的抑制。这些研究的结果将有助于我们进一步了解雌激素如何保护烧伤后的大脑，并可能提供一种新的，安全的，有效的临床治疗，以打击远程继发性烧伤的大脑和保护认知。
Patients with severe burn injury experience a rapid elevation in multiple circulating pro-inflammatory cytokines, with the levels correlating with both injury severity and outcome. Accumulations of these cytokines in animal models have been observed in remote organs, however data are lacking regarding early brain cytokine levels following burn injury, and the effects of estradiol on these levels. Using an experimental animal model, we studied the acute effects of a full-thickness third degree burn on brain levels of TNF-α, IL-1β, and IL-6 and the protective effects of acute estrogen treatment on these levels. Additionally, the acute administration of estrogen on regulation of inflammatory and apoptotic events in the brain following severe burn injury were studied through measuring the levels of phospho-ERK, phospho-Akt, active caspase-3, and PARP cleavage in the placebo and estrogen treated groups. In this study, 149 adult Sprague-Dawley male rats received 3rd degree 40% total body surface area (TBSA) burns. Fifteen minutes following burn injury, the animals received a subcutaneous injection of either placebo (n = 72) or 17 beta-estradiol (n = 72). Brains were harvested at 0.5, 1, 2, 4, 6, 8, 12, 18, and 24 hours after injury from the control (n = 5), placebo (n = 8/time point), and estrogen treated animals (n = 8/time point). The brain cytokine levels were measured using the ELISA method. In addition, we assessed the levels of phosphorylated-ERK, phosphorylated-Akt, active caspase-3, and the levels of cleaved PARP at the 24 hour time-point using Western blot analysis. In burned rats, 17 beta-estradiol significantly decreased the levels of brain tissue TNF-α (~25%), IL-1β (~60%), and IL-6 (~90%) when compared to the placebo group. In addition, we determined that in the estrogen-treated rats there was an increase in the levels of phospho-ERK (p < 0.01) and Akt (p < 0.05) at the 24 hour time-point, and that 17 beta-estradiol blocked the activation of caspase-3 (p < 0.01) and subsequent cleavage of PARP (p < 0.05). Following severe burn injury, estrogens decrease both brain inflammation and the activation of apoptosis, represented by an increase in the levels of phospho-Akt and inhibition of caspase-3 activation and PARP cleavage. Results from these studies will help further our understanding of how estrogens protect the brain following burn injury, and may provide a novel, safe, and effective clinical treatment to combat remote secondary burn injury in the brain and to preserve cognition.