PROJECT SUMMARY Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and predicts poor pulmonary and neurodevelopmental outcomes. Despite the well-documented association between inflammation and BPD, no safe and effective anti-inflammatory therapies to prevent BPD are currently available. How the neonatal innate immune response contributes to the pathogenesis of BPD is unknown, limiting therapeutic options. Our overarching aim is to determine the molecular mechanisms linking the neonatal innate immune response and impaired lung development that contributes to the pathogenesis of BPD. Importantly, recent studies in my laboratory identified a developmentally-regulated, hepatic-specific pattern of expression for key inhibitory proteins of the transcription factor NF?B. As NF?B plays a central role in regulating innate immunity, these findings have led us to propose a new organizing hypothesis linking the neonatal hepatic innate immune response to pulmonary injury. We hypothesize that the hepatic expression profile of the I?B family of NF?B inhibitory proteins results in a sustained pro-inflammatory innate immune response to systemic inflammatory stress that contributes to ongoing pulmonary inflammation, injury and impaired development. We propose three specific aims to test this hypothesis and determine the immunologic cross-talk between the developing lung and liver. In Aim 1, we will test whether the intracellular balance of I?B?/I?B? dictates the magnitude, duration and selectivity of the inflammatory-stress induced NF?B transcriptome. In Aim 2, we will test whether a robust and sustained pro-inflammatory neonatal innate immune response contributes to lung injury and abnormal development. In Aim 3, we will test whether inhibiting inflammatory stress-induced, I?B?-mediated hepatic NF?B signaling prevents prolonged pro-inflammatory gene expression and attenuates neonatal lung injury. Our hypothesis represents a paradigm shift in how we approach the prevention of BPD by linking a sustained pro-inflammatory neonatal innate immune response mediated by hepatic I?B?/NF?B signaling to lung injury and subsequent abnormal development. These studies will provide the foundation for translational work aimed at pharmacologically targeting I?B? /NF?B signaling to prevent BPD in at-risk infants.