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.
Despite advances in neonatal care, the incidence of bronchopulmonary dysplasia (BPD) has remained unchanged over the past 30 years. BPD resulting from perinatal lung injury predicts lifelong impairment in pulmonary function as well as poor neurodevelopmental outcomes. How the neonatal innate immune response contributes to lung injury and the development of BPD is unknown. This project will determine the molecular mechanisms linking the innate immune response to neonatal lung injury, so that new strategies can be developed to prevent BPD in at-risk infants.
|El Kasmi, Karim C; Vue, Padade M; Anderson, Aimee L et al. (2018) Macrophage-derived IL-1?/NF-?B signaling mediates parenteral nutrition-associated cholestasis. Nat Commun 9:1393|
|Dietz, Robert M; Wright, Clyde J (2018) Oxidative stress diseases unique to the perinatal period: A window into the developing innate immune response. Am J Reprod Immunol 79:e12787|
|Sherlock, Laurie G; Trumpie, Ashley; Hernandez-Lagunas, Laura et al. (2018) Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia. Antioxidants (Basel) 7:|
|Delaney, Cassidy; Sherlock, Laurie; Fisher, Susan et al. (2018) Serotonin 2A receptor inhibition protects against the development of pulmonary hypertension and pulmonary vascular remodeling in neonatal mice. Am J Physiol Lung Cell Mol Physiol 314:L871-L881|
|Wright, Clyde J; Sherlock, Laurie G; Sahni, Rakesh et al. (2018) Preventing Continuous Positive Airway Pressure Failure: Evidence-Based and Physiologically Sound Practices from Delivery Room to the Neonatal Intensive Care Unit. Clin Perinatol 45:257-271|
|McKenna, Sarah; Burey, Taylor; Sandoval, Jeryl et al. (2018) Immunotolerant p50/NF?B Signaling and Attenuated Hepatic IFN? Expression Increases Neonatal Sensitivity to Endotoxemia. Front Immunol 9:2210|
|McKenna, Sarah; Butler, Brittany; Jatana, Laurie et al. (2017) Inhibition of I?B?/NF?B signaling prevents LPS-induced IL1? expression without increasing apoptosis in the developing mouse lung. Pediatr Res 82:1064-1072|
|Rozance, Paul J; Wright, Clyde J (2017) Preparing for the first breath: in the developing lung, maternal overnutrition takes centre stage. J Physiol 595:6595-6596|