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A Safer Glucocorticoid to Treat Neonatal Lung Injury with Limited Adverse Neurologic Effects

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Bronchopulmonary dysplasia (BPD) remains a significant complication of prematurity affecting nearly 70% in infants born ?28 weeks. Current pharmacologic strategies to mitigate the development and progression of BPD include administration of long-acting synthetic glucocorticoids (sGCs) such as dexamethasone (Dex). Several randomized clinical trials establish that sGC therapy targeted to preterm infants with evolving lung injury decreases BPD risk substantially, but encumber significant risks related to adverse somatic growth and long-lasting alterations in brain structure and function. Therefore, there remains an urgent need for GC pharmacotherapy for BPD in neonates that will provide beneficial anti-inflammatory and lung maturation effects, but limited adverse effects on the brain. Ciclesonide (CIC) is a new generation inhaled sGC currently approved for the treatment of asthma and allergic rhinitis that does not cause systemic adverse effects often observed with other sGCs. Clinical trials also demonstrate no adverse effects of CIC beyond placebo in 2-year olds. We hypothesize that CIC will attenuate hyperoxia-mediated acute lung injury in neonates but NOT trigger the demyelination, astrogliosis, microglia activation or neuronal damage in neonatal brain caused by systemically administered sGCs such as Dex. Three Specific Aims are proposed to test this hypothesis with a multi-disciplinary team possessing the ability to simultaneously investigate in vitro mechanisms and highly relevant rodent models of neonatal lung injury. Aim 1 will determine the mechanisms by which CIC prevents hyperoxia-induced acute lung injury and alveolar remodeling in experimental BPD. Aim 2 will identify the transcriptomic responses to CIC within individual cell types of neonatal mouse lungs using scRNA-Seq. Aim 3 will compare the acute and long-term consequences of neonatal Dex versus CIC exposure on brain architecture and behavior. This study has potential to identify CIC as an effective sGC therapy for BPD with brain- sparing effects, addressing the current dearth of therapies to prevent and/or treat BPD in preterm infants.
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