Amelioration of Sepsis by Macrophage Activation

描述(申请人提供)：危重患者经常出现复杂的疾病谱，可能包括急性呼吸窘迫综合征、全身性炎症反应综合征、感染性休克和多器官功能障碍综合征。感染性休克的发生机制尚不完全清楚。因此，死亡率仍然高得令人无法接受，即28.6%。巨噬细胞A类清道夫受体(SRA)在巨噬细胞摄取修饰低密度脂蛋白、胆固醇酯蓄积以及在动脉粥样硬化形成中的作用而广为人知。然而，最近的证据表明，SRA作为一种先天性免疫受体发挥了作用。我们发现SRA在感染性休克的发病机制中也起着核心作用。具体地说，SRA增加了感染性休克的发病率和死亡率。这是SRA在败血症发病机制中的一个新的、新的作用。SRA介导败血症休克的机制涉及与败血症休克相关的促炎、促死亡表型的放大。此外，SRA通过结构性抑制TRIF/IRF？/IFN？而促进败血症后遗症的发生。支持生存的信号通路。除了这些重要的基础科学观察，我们的研究还为感染性休克的治疗和管理提出了新的和新的方法。我们假设：i)SRA通过放大感染性休克相关的促炎、促死亡表型在感染性休克的病理生理学中起关键作用；ii)SRA是TRIF/IRF？/IFN？促生存信号通路和III)SRA活性的调节和/或外源性干扰素的应用？将有助于败血症/感染性休克的管理和预防。我们将批判性地评估这些假设，具体目标如下。1.阐明SRA增强脓毒症/感染性休克促炎反应的机制。2.明确SRA抑制TRIF/IRF？/IFN？的机制。信号通路。3.确定SRA的短暂性拮抗和/或外源性干扰素的应用？将改善败血症后遗症，改善败血症休克的生存结局。这项研究的成功完成将使人们对脓毒症的细胞和分子机制有一个新的了解，并可能找到预防和治疗脓毒症/感染性休克的新的和新的方法。 公共卫生相关性：败血症、感染性休克和多器官衰竭是美国的主要临床问题。尽管进行了多年的密集研究，但关于这些毁灭性疾病的机制，我们仍然有许多不知道的地方。试图开发有效的治疗败血症/感染性休克和多器官衰竭的方法已被证明是极其困难的。这在一定程度上是由于我们对介导败血症损伤的细胞和机制的不完全了解。我们的新发现是巨噬细胞A类清道夫受体(SRA)在介导败血症/感染性休克的发病率和死亡率中起关键作用。就我们所知，这是SRA在疾病中的一个新的和新的角色。更有意义的是，我们对SR-A的研究提出了迄今为止意想不到的新方法来管理和治疗危重宿主的败血症/感染性休克。随着这项研究的完成，我们将对脓毒症的发病机制有一个新的了解，我们可能会找到治疗败血症/感染性休克的新的和新的方法。

DESCRIPTION (provided by applicant): The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, septic shock and multiple organ dysfunction syndrome. The mechanisms that lead to the development of septic shock are not fully understood. For this reason the mortality rate remains unacceptably high, i.e. 28.6%. The macrophage class a scavenger receptor (SRA) is best known for its role in the uptake of modified low density lipoprotein, accumulation of cholesteryl esters in macrophages and its role in atherogenesis. However, recent evidence has demonstrated a role for SRA as an innate immune receptor. We have discovered that SRA also plays a central role in the pathogenesis of septic shock. Specifically, SRA enhances the morbidity and mortality of septic shock. This is a new and novel role for SRA in the pathogenesis of septic disease. The mechanisms by which SRA mediates septic shock involves amplification of the pro-inflammatory, pro-death phenotype associated with septic shock. In addition, SRA facilitates septic sequelae by constitutively inhibiting the TRIF/IRF?/IFN? pro-survival signaling pathway. In addition to these important basic science observations, our studies have also suggested new and novel approaches for the treatment and management of septic shock. We hypothesize that: i) SRA plays a pivotal role in the pathophysiology of septic shock by amplifying the pro-inflammatory, pro-death phenotype associated with septic shock; ii) SRA is an endogenous inhibitor of the TRIF/IRF?/IFN? pro- survival signaling pathway and iii) Modulation of SRA activity and/or administration of exogenous IFN? will be useful in the management and prevention of sepsis/septic shock. We will critically evaluate these hypotheses with the following specific Aims. 1. Delineate the mechanisms by which SRA enhances the pro-inflammatory response to sepsis/septic shock. 2. Define the mechanisms by which SRA inhibits the TRIF/IRF?/IFN? signaling pathway. 3. Determine whether transient antagonism of SRA and/or administration of exogenous IFN? will ameliorate septic sequelae and improve survival outcome in septic shock. A successful completion of this research will result in a new understanding of the cellular and molecular mechanisms of sepsis and may also identify new and novel approaches for the prevention and treatment of sepsis/septic shock. PUBLIC HEALTH RELEVANCE: Sepsis, septic shock and multi-organ failure are major clinical problems in the United States. Despite years of intensive research, there is still much that we do not know about the mechanisms of these devastating diseases. Attempts at developing effective therapies for sepsis/septic shock and multi-organ failture have proven to be exceedingly difficult. This is due, in part, to our incomplete understanding of the cellular and mechanisms that mediate septic injury. We have made the novel observation that the macrophage class a scavenger receptor (SRA) plays a key role in mediating the morbidity and mortality of sepsis/septic shock. To the best of our knowledge, this is a new and novel role for SRA in disease. Of greater significance, our studies with SR-A have suggested new, and heretofore unanticipated, approaches to the management and treatment of sepsis/septic shock in the critically ill host. At the completion of this research we will have gained a new understanding of the mechanisms of sepsis and we may identify new and novel approaches for the treatment of sepsis/septic shock.