Immunosuppression after cardiac arrest and resuscitation

摘要 由于在复苏方面取得了相当大的进展，心脏骤停(CA)患者在最初的 被逮捕并被送入重症监护病房(ICU)的人数一直在稳步增加。然而，在这一增长中， 在患者群体中，发病率和死亡率仍然高得令人无法接受。这主要归因于 CA后综合征，免疫反应失衡是其关键组成部分。利用我们的临床相关性 CA和心肺复苏(CA/CPR)的小鼠模型，我们最近发现： CA/CPR，从公认的CA后急性促炎免疫反应明显转变为 鲜为人知的抗炎免疫反应，最终演变为严重的免疫抑制 州政府。此外，我们的初步数据清楚地支持这种免疫抑制状态与CA术后之间的联系 感染，功能恢复差。重要的是，临床观察证实了这一观点。 CA幸存者中发生感染并发症的比例很高，复苏后感染被认为 以增加发病率和死亡率。因此，更好地认识术后并发症具有重要的临床意义。 CA免疫抑制。我们的长期目标是开发新的治疗策略来改善CA的预后。 这里的目标是剖析CA后免疫抑制的基础机制，并确定 CA后靶向免疫抑制对CA预后的影响，包括感染发生率和长期疗效 功能恢复。值得注意的是，我们的试点研究提供了令人信服的证据表明， 下丘脑-垂体-肾上腺(HPA)轴是CA术后免疫抑制的主要机制。我们的 中心假说是CA和复苏激活了大脑中的炎症体，进而激活了 HPA轴，导致免疫抑制和不良的CA结局。这一假设是基于我们强大的 初步数据和与疾病诱导的免疫抑制相关的大量文献。我们将测试我们的 通过追求以下具体目标的中心假设：1)确定HPA轴在CA后的作用 免疫抑制：2)通过HPA轴确定炎症小体在CA术后免疫抑制中的作用； 3)确定CA后免疫抑制的调节对CA转归的影响。建议数 研究意义重大，因为我们将从这项研究中获得的知识有望为未来的发展提供信息 新的复苏后护理策略，以减轻CA后免疫功能障碍的有害影响，因此， 改善CA的整体预后。

Abstract Due to considerable advances in resuscitation, the number of cardiac arrest (CA) patients who survive the initial arrest and are admitted to the intensive care unit (ICU) has been steadily increasing. However, among this growing patient population, the morbidity and mortality rates remain unacceptably high. This has been attributed primarily to post-CA syndrome of which an imbalanced immune response is a key component. Using our clinically relevant murine model of CA and cardiopulmonary resuscitation (CA/CPR), we recently discovered that following CA/CPR, there is a clear shift from the well-established acute post-CA pro-inflammatory immune response to the less-known anti-inflammatory immune response, which eventually evolves into a severe immunosuppressive state. Further, our preliminary data clearly support a link between this immunosuppressive state, and post-CA infection and poor functional recovery. Importantly, this notion is corroborated by clinical observations that infectious complications occur in a high percentage of CA survivors, and post-resuscitation infection is believed to increase morbidity and mortality. Therefore, it is of tremendous clinical significance to better understand post- CA immunosuppression. Our long-term goal is to develop novel therapeutic strategies to improve CA prognosis. The objective here is to dissect mechanisms that underpin post-CA immunosuppression, and to determine the effects of targeting post-CA immunosuppression on CA outcome, including incidence of infections and long-term functional recovery. Notably, our pilot studies have provided compelling evidence indicating that activation of the hypothalamic-pituitary-adrenal (HPA) axis is a primary mechanism that drives post-CA immunosuppression. Our central hypothesis is that CA and resuscitation activates inflammasomes in the brain, which in turn activates the HPA axis, leading to immunosuppression and poor CA outcome. This hypothesis is based on our strong preliminary data and on substantial literature related to disease-induced immunosuppression. We will test our central hypothesis by pursuing the following specific aims: 1) Determine the role of the HPA axis in post-CA immunosuppression; 2) Determine the role of inflammasomes in post-CA immunosuppression via the HPA axis; and 3) Determine the effects of modulating post-CA immunosuppression on CA outcomes. The proposed research is significant because knowledge we will gain from this study is expected to inform future development of new post-resuscitation care strategies to mitigate detrimental effects of post-CA immune dysfunction and thus, improve overall CA prognosis.