Inflammation resolving mechanism dysregulation in postoperative cognitive decline

描述（由申请人提供）：我们担心高龄手术患者可能会在手术后很长时间内出现处理信息的问题（“认知功能障碍”）。除了年龄之外，最近的一项研究表明，患有代谢综合征（一种包括内脏肥胖、胰岛素抵抗、血脂异常和高血压的疾病）的手术患者特别容易出现术后认知功能障碍，发生频率几乎为三分之一。在过去的5年里，我们从一系列已发表的研究中积累了数据，这些研究涉及接受手术的健康啮齿动物，揭示了海马体中短暂炎症的发展，海马体是大脑中对认知功能至关重要的区域。因此，手术前获得的急性记忆被打断了。正常情况下，大脑炎症和记忆衰退都会在几天内修复，不会产生长期的后果。然而，如果解决炎症的过程被禁用，那么正常认知功能的恢复将不会发生。我们对代谢综合征的大鼠模型进行了术后研究，其中自然和养育的影响都会导致严重后果，包括预期寿命大大缩短。急性术后，这些大鼠出现了严重的认知能力下降，并伴有更严重的脑部炎症，这种认知能力下降远不止是短暂的，而是持续的。我们注意到，认知退化与这些动物解决手术创伤后炎症的方式异常有关。我们的新项目验证了炎症消退异常是导致代谢综合征大鼠模型术后认知能力严重且持续下降的原因。当我们测试这种因果关系时，我们将发现免疫系统中可能的目标，这将使我们能够干预并有希望中断这种异常。特别值得鼓励的是，我们注意到的一些异常是可以通过运动逆转的，因此我们也将探索运动训练对术后认知能力下降的机制和表达的影响。由于大鼠模型和人类代谢综合征之间的相似性，我们随后计划研究患有这种疾病的手术患者是否表现出与我们在大鼠中注意到的相同的异常；如果是这样，我们可以将这项研究中提到的成功的治疗干预措施扩展到人类，特别是术前锻炼。

DESCRIPTION (provided by applicant): There is a concern that surgical patients of advanced age may develop problems processing information ("cognitive dysfunction") that persist long after the operation. Apart from age a recent study revealed that surgical patients with the Metabolic Syndrome (a clustering of conditions that include visceral obesity, insulin resistance, dyslipidemia and hypertension) are particularly prone to develop postoperative cognitive dysfunction occurring with a frequency of almost one in three. Over the last 5 years we have accumulated data from a series of published studies involving healthy rodents undergoing surgery that reveal the development of short-lived inflammation in the hippocampus, a brain region that is vital for cognitive function. As a consequence acute recall of memories, acquired immediately before the surgery, is disrupted. Normally, both the brain inflammation and the memory decline are repaired within days with no long-lasting consequence. However, if the processes involved in resolving the inflammation are disabled then restoration of normal cognitive function will not occur. We have undertaken postoperative studies involving a rat model of the Metabolic Syndrome in which both the influences of nature and nurture contribute to serious consequences including a considerably shorter life expectancy. Acutely postoperatively, these rats develop exaggerated cognitive decline, and remotely a persistent, rather than short-lived, cognitive decline that is associated with more severe brain inflammation. We noted that the cognitive deterioration was associated with abnormalities in the manner that these animals resolve the inflammation that follows the trauma of surgery. Our new project tests the hypothesis that the abnormalities in inflammation-resolution are the cause for the exaggerated and persistent postoperative cognitive decline in this rat model of the Metabolic Syndrome. As we test this cause and effect relationship we will uncover possible targets in the immune system that will allow us to intervene and hopefully interrupt the abnormality. In particular, we are encouraged that some of the abnormalities that we have noted are potentially reversible with exercise and therefore we will also explore the effect of exercise training on the mechanisms and expression of postoperative cognitive decline. Because of the similarity between the rat model and the human condition of Metabolic Syndrome we subsequently plan to study whether surgical patients with this condition exhibit the same abnormalities as we noted in the rat; if so, we can extend to humans successful therapeutic interventions noted in this study, in particular pre-operative exercise.