Evaluating Resolution Mechanisms for Infectious Inflammation

项目摘要/摘要 在美国，败血症是一个重大的公共卫生问题，有着巨大的经济负担。死亡率令人担忧 败血症复发率高。无论是通过创伤还是医院感染，微生物都可能导致失控 影响数百万人的感染性炎症。因此，需要更深入地了解内生性 解决机制及其在解决败血症方面的潜在失败(S)。急性炎症反应 具有保护性；然而，如果不加以控制，炎症与许多疾病、创伤和外科手术有关 可能导致败血症和生命损失的干预措施。炎症的消退被广泛认为是一种 被动应对和今天被认为是一个令人兴奋的、基本上未被开发的新干预领域。 在自限性炎症中，PI首先定位和阐明了细胞的结构、生物合成和功能。 新型拆分相介体统称为专门化的促拆分介体(SPM)。 SPM超家族包括脂氧素、溶血素、保护素和松脂，每个家族都被证明 积极刺激炎症、感染的消退，并具有器官保护作用(即肺、心脏、 神经保护)在临床前动物模型中。在人体组织中，对细胞和分子的理解 为了控制内源性化学物质，迫切需要感染性炎症的解决方案 解决细菌挑战的先天反应的信号。SPM靶向人类中性粒细胞和 巨噬细胞在启动防御的炎症反应以及及时化解炎症反应中起着中心作用。 在此R35 Mira应用中，PI应专注于解决以下领域的关键差距和挑战 解决与人类感染性炎症、败血症和复发有关的炎症。主 要解决的首要问题和挑战集中在确定是否 炎症分解机制的失败会导致败血症或其复发的不良结局，并 确定这些新组件。此信息是非常需要的，必须从可访问的 人体组织，如血液，以便它们可以迅速实施。这些结果将有助于分层和 为监测解决机制和途径以及其 人类败血症的潜在失败。解决这些关于炎症消退的基本问题是 此Mira应用程序的主旨是使用新的创新方法和技术在 放置在PI的实验室中，由NIGMS支持。PI具有创新的记录，以及 MIRA将使人们能够获得有关SPM在解决传染病方面的机制的关键新信息 炎症需要长期，以开展知情的败血症和新的治疗方法 涉及并将需要考虑到复原力和应对措施的其他疾病 发炎。

Project Summary/Abstract Sepsis is a significant public health concern with substantial financial burden in the USA. Mortality is alarmingly high in sepsis recurrence. Whether by trauma or nosocomial infection, microbes can give rise to uncontrolled infectious inflammation that impacts millions. Therefore, a deeper knowledge is needed of the endogenous resolution mechanisms as well as their potential failure(s) to resolve sepsis. The acute inflammatory response is protective; yet, when uncontrolled, inflammation is associated with many diseases, trauma, and surgical interventions that can lead to sepsis and loss of life. Resolution of inflammation was widely held to be a passive response and today is considered an exciting and essentially untapped terrain for new interventions. In self-limited inflammation, the PI first mapped and elucidated the structures, biosynthesis and functions of novel families of resolution phase mediators collectively termed specialized pro-resolving mediators (SPM). The SPM superfamily include lipoxins, resolvins, protectins and maresins where each family is proven to actively stimulate the resolution of inflammation, infections and are organ protective (i.e. lung, heart, neuroprotective) in pre-clinical animal models. In human tissues, cellular and molecular understanding of resolution programs for infectious inflammation is critically needed to harness the endogenous chemical signals that resolve innate responses to bacterial challenge. SPM target both human neutrophils and macrophages that are central in initiating the inflammatory response for defense as well as its timely resolution. In this R35 MIRA application, the PI shall focus on addressing critical gaps and challenges in the field of resolution of inflammation relevant to human infectious inflammation, sepsis and recurrence. The main overarching question and challenge to be addressed focuses on the general mission of determining whether failed resolution mechanisms in inflammation contribute to poor outcomes in sepsis or its recurrence and to identify these new components. This information is critically needed and must be obtained from accessible human tissues such as blood so that they can be swiftly implemented. Results from these will help stratify and shape the basis of new strategies for monitoring resolution mechanisms and pathways as well as their potential failure in human sepsis. Addressing these fundamental questions on the resolution of inflammation is the thrust of this MIRA application and are designed using new innovative approaches and technologies in place in the PI’s laboratory from NIGMS support. The PI has a record of innovation, and the flexibility of a MIRA will enable obtaining critical new information on mechanisms of SPM in resolution of infectious inflammation needed in the long-term, to carry out well-informed new treatment approaches for sepsis and other maladies that involve and will require taking into account resilience and the resolution response in inflammation.