Evaluating Resolution Mechanisms for Infectious Inflammation

项目总结/摘要 败血症是美国一个重大的公共卫生问题，给美国带来沉重的经济负担。死亡率惊人地 脓毒症复发率高无论是通过创伤还是医院感染，微生物都可以引起不受控制的 影响数百万人的传染性炎症因此，需要对内源性的 解决机制以及其解决脓毒症的潜在失败。急性炎症反应 是保护性的;然而，当不受控制时，炎症与许多疾病、创伤和手术有关。 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 被动反应，今天被认为是新干预措施的一个令人兴奋和基本上尚未开发的领域。 在自限性炎症中，PI首先绘制并阐明了 新的消退相介质家族统称为特化促消退介质（SPM）。 SPM超家族包括脂氧素、消退素、保护素和maresins， 积极刺激炎症、感染的消退，并且是器官保护性的（即肺，心脏， 神经保护）。在人体组织中，细胞和分子的理解， 感染性炎症的解决方案是迫切需要的，以利用内源性化学物质， 解决对细菌挑战的先天反应的信号。SPM靶向人中性粒细胞和 巨噬细胞是启动炎症反应防御以及及时解决的中心。 在本R35 MIRA申请中，PI应重点解决以下领域的关键差距和挑战： 与人类感染性炎症、脓毒症和复发相关的炎症消退。主要 要解决的首要问题和挑战集中在确定是否 炎症中的失败的消退机制导致脓毒症或其复发的不良结果， 识别这些新组件。这些信息是迫切需要的，必须从可访问的 例如血液等人体组织，以便它们可以迅速实施。这些结果将有助于分层， 为监测解决机制和途径及其 在人类败血症中可能失败。解决这些关于炎症的根本问题是 该MIRA应用程序的主旨，并使用新的创新方法和技术设计， NIGMS支持的PI实验室。PI有创新的记录，以及一个 MIRA将能够获得关于SPM在解决传染性疾病方面的机制的重要新信息。 炎症需要在长期内，进行充分知情的新的治疗方法，脓毒症和 其他涉及并需要考虑弹性和解决响应的疾病， 炎症

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.