Delineating Pulmonary Cellular Responses to Prenatal Chorioamnionitis and Postnatal Hyperoxia
Bronchopulmonary dysplasia (BPD) is the most common cause of death and neurodevelopmental impairment in preterm infants for which no cure currently exists. Preterm infants who are exposed to infection in the prenatal period, a condition called chorioamnionitis, often require treatment with oxygen and mechanical ventilation in the postnatal period and have more severe BPD. Clinical observations and preclinical studies suggest that prenatal exposure to inflammation might amplify postnatal lung response to oxidative stress, but the underlying mechanisms are unclear. Understanding the mechanism by which chorioamnionitis amplifies oxygen-induced lung injury will help develop individualized therapeutic strategies to prevent BPD in this specific subset of preterm infants. Since the lung is a complex organ composed of many different cell types with distinct transcriptomics and cell functions, the primary objective of this study is to identify cell-specific phenotypic and transcriptomic differences in response to the interactive effects of prenatal and postnatal inflammation. We hypothesize that intrauterine exposure to inflammation amplifies postnatal oxygen-induced impairment of alveolar and vascular development by modulating distinct pulmonary cell-specific differential gene expression. We will use a well-established neonatal rat model of prenatal exposure to lipopolysaccharide and postnatal exposure to high concentrations of oxygen to evaluate the interactive effects of prenatal inflammation and postnatal oxidative stress on the major pulmonary cell types. To date, preclinical studies examining mechanisms of BPD have only evaluated whole lung homogenates. Our study is the first to specifically elucidate cell-specific phenotypic and transcriptomic changes induced by the interactive effects of prenatal inflammation and postnatal oxidative injury to the lung. Results of this study will provide a framework of cellular responses to combined prenatal and postnatal lung injury that are distinct to key pulmonary cell types and provide an evidence-based foundation for future mechanistic studies for development of novel therapeutics for treatment of BPD.