Department of Neurology, University of California, San Francisco, CA, USA.
Neurobiol Dis. 2013 Oct;58:289-95. doi: 10.1016/j.nbd.2013.06.012. Epub 2013 Jun 29.
Traumatic brain injury (TBI) causes disruption of the blood brain barrier (BBB) leading to hemorrhage which can complicate an already catastrophic illness. Matrix metalloproteinases (MMPs) involved in the breakdown of the extracellular matrix may lead to brain hemorrhage. We explore the contribution of the 70 kDa heat shock protein (Hsp70) to outcome and brain hemorrhage in a model of TBI. Male, wildtype (Wt), Hsp70 knockout (Ko) and transgenic (Tg) mice were subjected to TBI using controlled cortical impact (CCI). Motor function, brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. Brains were evaluated for the effects of Hsp70 on MMPs. In Hsp70 Tg mice, CCI led to smaller brain lesions, decreased hemorrhage and reduced expression and activation of MMPs compared to Wt. CCI also significantly decreased right-biased swings and corner turns in the Hsp70 Tg mice. Conversely, Hsp70 Ko mice had significantly increased lesion size, worsened brain hemorrhage and increased expression and activation of MMPs with worsened behavioral outcomes compared to Wt. Hsp70 is protective in experimental TBI. To our knowledge, this is the direct demonstration of brain protection by Hsp70 in a TBI model. Our data demonstrate a new mechanism linking TBI-induced hemorrhage and neuronal injury to the suppression of MMPs by Hsp70, and support the development of Hsp70 enhancing strategies for the treatment of TBI.
创伤性脑损伤（TBI）导致血脑屏障（BBB）破坏，导致出血，这可能使已经灾难性的疾病复杂化。参与细胞外基质分解的基质金属蛋白酶（MMPs）可能导致脑出血。我们在 TBI 模型中探索 70 kDa 热休克蛋白（Hsp70）对结果和脑出血的贡献。雄性野生型（Wt）、Hsp70 敲除（Ko）和转基因（Tg）小鼠使用皮质撞击控制装置（CCI）接受 TBI。在 3、7 和 14 天时评估运动功能、脑出血和病变大小。评估 Hsp70 对 MMPs 的影响。与 Wt 相比，Hsp70 Tg 小鼠的 CCI 导致较小的脑损伤、较少的出血以及 MMPs 的表达和激活减少。CCI 还显著减少了 Hsp70 Tg 小鼠的右侧摆动和角落转弯。相反，与 Wt 相比，Hsp70 Ko 小鼠的病变大小明显增加，脑出血加重，MMPs 的表达和激活增加，行为结果恶化。Hsp70 在实验性 TBI 中具有保护作用。据我们所知，这是 Hsp70 在 TBI 模型中直接证明脑保护的首次报道。我们的数据表明了一种新的机制，将 TBI 诱导的出血和神经元损伤与 Hsp70 抑制 MMPs 联系起来，并支持开发 Hsp70 增强策略来治疗 TBI。
