Reducing Pathological Macrophage Activation and White Matter Injury in Neonatal Intraventricular Hemorrhage

The goal of this project is to reduce white matter loss and improve neurological outcomes in neonatal IVH. Even a small increase in OPC survival could confer a large functional benefit as OPCs persist and maintain their proliferative capacity into adulthood6. Our expertise in macrophage phenotyping, neuropharmacology, and animal models allows us to conduct the appropriate experiments to better understand macrophage activation and OPC survival in neonatal brain injury. We hypothesize that M1 macrophage activation and TNFá release after neonatal IVH reduces the number of viable OPCs and results in white matter deficiency in adulthood. Using azithromycin to shift activated macrophages towards a beneficial M2 phenotype may be a strategy for reducing white matter pathology in the developing brain of infants with IVH. If our experiments successfully link neonatal IVH to neuroinflammation-induced OPC death, and azithromycin improves neurobehavioral outcomes, we will have rationale for clinical studies of azithromycin in neonatal IVH. Our institution has already conducted clinical studies of azithromycin for neonatal inflammatory lung injury and our neonatal intensive care unit will be expanding in 2018. This, combined with our expertise in white matter injury and neuroinflammation make the University of Kentucky the ideal institution to advance the treatment of neonatal IVH. The development of a pharmacologic therapy for neonatal brain injury would have a major impact on neonatal neurological care and improve upon current supportive therapies.