Amelioration of Sepsis by Macrophage Activation

通过巨噬细胞激活改善脓毒症

• 批准号: 8235529
• 负责人: David L. Williams
• 金额: $ 28.71万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235529
• 关键词: Acute; Adult Respiratory Distress Syndrome; Applications Grants; Basic Science; Cessation of life; Cholesterol Esters; Clinical; Complex; Critical Illness; Data; Development; Disease; Event; Functional disorder; Genetic; Goals; Grant; IRF3 gene; Immune System Diseases; Immune system; Immunologic Receptors; Infection; Inflammatory; Inflammatory Response; Injury; Interferons; Lead; Ligation; Light; Literature; Low-Density Lipoproteins; Macrophage Activation; Mediating; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Organ; Organ failure; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Play; Prevention; Puncture procedure; Reporting; Research; Role; SR-A proteins; Sepsis; Sepsis Syndrome; Septic Shock; Signal Pathway; TLR4 gene; Trauma; Treatment Efficacy; United States; Work; atherogenesis; base; clinically relevant; effective therapy; improved; inhibitor/antagonist; macrophage; mortality; novel; novel strategies; prevent; research study; scavenger receptor; septic; uptake

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.

描述（由申请人提供）：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、全身炎症反应综合征、感染性休克和多器官功能障碍综合征。导致败血性休克发展的机制尚未完全了解。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）最为人所知的是其在修饰的低密度脂蛋白的摄取、胆固醇酯在巨噬细胞中的积累以及其在动脉粥样硬化形成中的作用。然而，最近的证据表明SRA作为先天免疫受体的作用。我们发现SRA在感染性休克的发病机制中也起着重要作用。特别是，SRA增加了感染性休克的发病率和死亡率。这是SRA在脓毒症发病机制中的一个新的和新颖的作用。SRA介导败血性休克的机制涉及与败血性休克相关的促炎性、促死亡表型的扩增。此外，SRA通过组成性抑制TRIF/IRF？/干扰素？促生存信号通路。除了这些重要的基础科学观察，我们的研究还提出了治疗和管理感染性休克的新方法。我们假设：i）SRA通过放大与脓毒性休克相关的促炎、促死亡表型在脓毒性休克的病理生理学中起关键作用; ii）SRA是TRIF/IRF？/干扰素？促生存信号通路和iii）SRA活性的调节和/或外源性IFN？将可用于脓毒症/脓毒性休克的管理和预防。我们将严格评估这些假设与以下具体目标。1.描述SRA增强脓毒症/脓毒性休克促炎反应的机制。2.定义SRA抑制TRIF/IRF的机制？/干扰素？信号通路3.确定是否瞬时拮抗SRA和/或外源性IFN的管理？将改善脓毒性后遗症并改善脓毒性休克的存活结果。这项研究的成功完成将导致对脓毒症的细胞和分子机制的新理解，也可能确定预防和治疗脓毒症/脓毒性休克的新方法。 公共卫生相关性：脓毒症、脓毒性休克和多器官衰竭是美国的主要临床问题。尽管经过多年的深入研究，我们对这些毁灭性疾病的机制仍然有很多不了解。已经证明，开发用于脓毒症/脓毒性休克和多器官衰竭的有效疗法的尝试是极其困难的。这部分是由于我们对介导脓毒性损伤的细胞和机制的不完全理解。我们发现巨噬细胞A类清道夫受体（macrophage class a scavenger receptor，SRA）在介导脓毒症/脓毒性休克的发病率和死亡率中起关键作用。据我们所知，这是SRA在疾病中的一个新的和新颖的作用。更重要的是，我们对SR-A的研究提出了新的、迄今为止未预料到的方法来管理和治疗危重宿主中的脓毒症/脓毒性休克。本研究完成后，我们将对脓毒症的机制有一个新的认识，我们可能会发现治疗脓毒症/脓毒性休克的新方法。