Evaluating Resolution Mechanisms for Infectious Inflammation

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.