Role of Cytokines in Sepsis and Trauma

描述（由申请人提供）：脓毒症仍然是一个严重的临床问题，具有显著的发病率和死亡率，即使经过广泛的研究，在我们对疾病过程的基本机制的理解中仍存在重要的未解决的问题。以前的治疗尝试主要是针对全面钝化脓毒症的炎症反应。我们使用盲肠结扎穿孔（CLP）诱导的脓毒症小鼠模型来仔细检查基本机制，并发现脓毒症早期（前5天）和晚期（超过5天）之间的重要差异。CLP可以以导致50%死亡率的方式进行，但挑战是准确预测哪些小鼠将存活。与具有100%致死率的模型相比，具有50%致死率的CLP模型提供了更大的洞察力，因为治疗可能增加或减少存活率，使得研究结果更具临床相关性。我们已经确定了准确预测5天脓毒症生存的生物标志物。这些生物标志物允许在小鼠中进行研究，即使在几年前也不可行。在败血症的前5天内，可在动物死亡前处死动物，并进行分析以评价随后死亡的机制。具体目标之一将试图通过增强中性粒细胞早期募集到腹膜腔中以帮助根除感染病灶来提高存活率。将进行毒性研究，以解决局部中性粒细胞水平升高是否会导致实质性器官损伤的问题。具体目标二将着眼于是否增加水平的天然存在的IgM抗体针对肠道细菌作为一个主要的决定因素的结果。这符合以下假设：脓毒症应答的复杂性的一部分是在脓毒症发作之前存在循环抗体，其将使细菌蛋白化以增强其吞噬作用并被中性粒细胞杀死。在第三个具体目标中，我们将使用我们用于在脓毒症的早期阶段测量细胞因子的新型多重形式来评估脓毒症的早期阶段中的个体定制治疗。我们的工作已经确定了准确预测随后死亡率的关键血浆细胞因子水平。只有那些在致死性范围内升高的细胞因子才会被阻断，而不是像高剂量糖皮质激素那样全面钝化炎症。最后一个具体目标将着眼于脓毒症的慢性阶段，即CLP后5天以后发生的阶段。这些小鼠中的一些死于过度炎症，而另一些死于迟钝的炎症反应。再次使用多重方法，我们将为个体动物定制治疗。我们的总体假设是脓毒性炎症反应是动态的，最佳治疗需要个体化或针对早期根除细菌。外行语言：许多患者仍然死于严重的细菌感染，即使他们用正确的抗生素治疗。目前尚不清楚这些患者死亡的原因。我们将使用动物模型来确定细菌如何伤害\杀死患者以及如何预防这种情况。公共卫生相关性：即使使用正确的抗生素治疗，许多患者仍然死于严重的细菌感染。目前尚不清楚这些患者死亡的原因，也不清楚治疗这些患者的最佳方法。我们将使用动物模型来帮助我们了解细菌如何杀死患者以及如何预防这种情况。

DESCRIPTION (provided by applicant): Sepsis remains a serious clinical problem with substantial morbidity and mortality and even after extensive investigation there are important, unresolved issues in our understanding of the basic mechanisms of the disease process. Previous attempts at therapy were mostly directed at globally blunting the inflammatory response to sepsis. We have used the murine model of sepsis induced by cecal ligation and puncture (CLP) to closely examine basic mechanisms and find important differences between the early (first 5 days) and late phase of sepsis (beyond day 5). CLP may be performed in a manner to cause 50% mortality but a challenge has been to predict accurately which mice will live. A CLP model with 50% lethality provides much greater insight compared to a model with 100% lethality since therapies may increase or decrease survival, making the findings more clinically relevant. We have identified biomarkers which accurately predict 5 day sepsis survival. These biomarkers allow studies in mice which were not feasible even a few years ago. Animals may be sacrificed during the first 5 days of sepsis prior to their demise and analyses performed to evaluate mechanisms of subsequent mortality. Specific aim one will attempt to improve survival by enhancing early recruitment of neutrophils into the peritoneal cavity to help eradicate the focus of infection. Toxicity studies will be performed to address the issue of whether increasing local levels of neutrophils contributes to substantial organ injury. Specific aim two will look at whether increased levels of naturally occurring IgM antibodies directed against enteric bacteria serve as a primary determinant of outcome. This fits with the hypothesis that a portion of the complexity of the response to sepsis is the presence of circulating antibodies prior to the onset of sepsis which would opzonize bacteria to enhance their phagocytosis and killing by the neutrophils. In the third specific aim we will evaluate individually tailoring therapy in the early stages of sepsis using our novel multiplex format for measuring cytokines during the early phase of sepsis. Our work has identified critical plasma cytokine levels that accurately predict subsequent mortality. Only those cytokines which are elevated in the range associated with lethality will be blocked, rather than globally blunting inflammation such as occurs with high-dose glucocorticoids. The last specific aim will look at the chronic phase of sepsis, that which occurs beyond day 5 after CLP. Some of these mice died with excessive inflammation and some of them died with a blunted inflammatory response. Again using the multiplex approach we will tailor the therapy to the individual animal. Our overarching hypothesis is that the septic inflammatory response is dynamic and optimal therapy needs to be individually tailored or directed to early eradication of bacteria. Lay Language: Many patients still die from severe bacterial infections even when they are treated with the correct antibiotics. It is not clear why these patients die. We will use an animal model to determine how bacteria injure\kill patients and how to prevent this. PUBLIC HEALTH RELEVANCE: Many patients still die from severe bacterial infections even when they are treated with the correct antibiotics. It is not clear why these patients die, or the best method to treat the patients. We will use an animal model to help us understand how bacteria kill patients and how to prevent this.