The overall goal of this proposal is to better understand how anti-inflammatory agents can affect outcomes in term and preterm septic newborns. Approximately 1 million newborns die annually worldwide due to severe infections and sepsis. This risk is particularly high among preterm newborns who represent 11% of all live births globally. The distinct neonatal inflammatory immune response to severe infections has been associated with increased mortality and multiple organ injury including long-term neurodevelopmental impairment. Neonatal sepsis frequently results in death or major disability even with timely antimicrobial treatment, and little progress has been made to alleviate it over the past three decades. There continues to be an urgent unmet medical need to prevent and/or treat hyper-inflammation associated with sepsis in the newborn, and the ability to non- invasively monitor treatment effects on the central nervous system. The immunomodulatory phosphodiesterase inhibitor pentoxifylline (PTX), which could potentially be licensed for use in neonates, has shown promise as an anti-inflammatory agent in addition to antibiotics in small human trials. To date, little is known regarding its systemic and central nervous system-specific immune-modulatory effects in preterm and term neonates. PTX interactions with other commonly employed anti-inflammatory and anti-infective agents remain unexplored. We propose to characterize the age-specific actions of PTX on bacteria-induced pro- and anti-inflammatory immune responses in a newborn mouse sepsis model in vivo. The inhibitory effects of PTX, alone or in combination with other immune-modulatory agents, on bacteria-induced innate inflammatory responses will be investigated.
The aims of this project are: (1) To characterize the effects of PTX, alone or in combination with other anti- inflammatory agents (inflammasome inhibitors), on systemic production of inflammatory mediators and on mortality in a neonatal term and preterm bacterial sepsis mouse model. (2a) To investigate the acute immunomodulatory effects of PTX on inflammatory responses in the brain in murine neonatal sepsis. (2b) To explore the feasibility and sensitivity of in vivo positron emission tomography (PET) imaging to non-invasively detect and quantify bacterial infection in the brain and response to therapies in septic neonatal rodents. Overall, successful completion of these studies will advance our understanding of early life immune development and its pharmacological modification. Findings from this project will aid in establishing anti-inflammatory strategies such as PTX that target exaggerated neonatal host immune responses as part of a more comprehensive approach to newborn sepsis therapy. Furthermore, successful application of in vivo PET imaging of cerebral infection will enable us to conduct future longitudinal studies to investigate the outcomes of neonatal central nervous system infections and its treatment with subsequent neurobehavioral impairment and structural neuronal alterations.
There is an unmet medical need to prevent and treat harmful inflammation associated with sepsis in the newborn, for which pentoxifylline is a promising candidate anti-inflammatory therapy in addition to antibiotics. This project will characterize age-specific actions of pentoxifylline on bacteria-induced inflammatory responses in the blood and brain of septic newborn mice. The project will also explore the ability of positron emission tomography imaging to non-invasively detect and quantify bacterial infection in the brain of septic animals.