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

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Principal Investigator: Donald B DeFranco
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $579,211
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development

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.

Terms: <0-11 years old><2 year old><2 years of age><21+ years old><5 year old><5 years of age><Academy><Acute><Acute Lung Injury><Acute Pulmonary Injury><Address><Adrenal Glands><Adrenals><Adult><Adult Human><Adverse effects><Affect><Agonist><Air><Ali-esterase><Allergic rhinitis><Allergic rhinitis due to allergen><Allergic rhinosinusitis><Alveolar><American><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Architecture><Asthma><Atopic rhinitis><Attenuated><B-esterase><Behavior><Bone Growth><Brain><Brain Nervous System><Bronchial Asthma><Bronchopulmonary Dysplasia><CAP-hydrolyzing Enzyme><Capsaicin-Hydrolyzing Enzyme><Carboxyesterase><Carboxylate Esterase><Carboxylester Lipase><Carboxylesterase B><Carboxylesterases><Carboxylic Ester Hydrolase><Carboxylic Ester Hydrolases><Cerebral Palsy><Child><Child Youth><Childhood><Children (0-21)><Clinical Practice Guideline><Clinical Trials><Complication><Demyelinations><Development><Dexamethasone><Dose><Drug Precursors><Drug Therapy><Drugs><Encephalon><Engineering / Architecture><Fatty Acids><Fibrosis><Generalized Growth><Generations><Glucocorticoid Receptor><Glucocorticoids><Goals><Growth><Hortega cell><Hyperoxia><In Vitro><Individual><Infant><Inflammation><Inhalation><Inhaling><Injury><Isocarboxazid amidase><Liquid Chromatography><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Medication><Microglia><Molecular><Naproxen Esterase><Neonatal><Neonatal lung><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurologic><Neurologic Effect><Neurological><Neurons><Non-specific Carboxylesterase><Non-specific Esterase><Nonspecific Esterase><Oligo><Oligonucleotides><Patients><Pediatrics><Pharmaceutical Preparations><Pharmacotherapy><Placebos><Pneumonitis><Premature Infant><Pro-Drugs><Procaine Esterase><Prodrugs><Pulmonary Inflammation><Recommendation><Resolution><Rhinitis allergic atopic><Risk><Rodent Model><Sham Treatment><Structure><Testing><Therapeutic><Tissue Growth><Vulnerable Populations><adulthood><age 2 years><age 5 years><aged 2 years><aged two years><astrogliosis><attenuate><attenuates><carboxylesterase><cell type><chronic lung disease in infants><chronic lung disease in neonatal infants><chronic lung disease in neonates><chronic lung disease in newborns><chronic lung disease in prematurity><chronic lung disease in preterm infants><chronic lung disease of infancy><chronic lung disease of prematurity><clinical practice and guidelines><demyelinate><developmental><dosage><drug treatment><drug/agent><extreme prematurity><extremely premature infant><extremely preterm><extremely preterm infant><five year old><five years of age><gitter cell><hyperoxygenation><infant chronic lung disease><infants born premature><infants born prematurely><infants with chronic lung disease><injuries><innovate><innovation><innovative><kids><long bone><lung injury><lung maturation><mesoglia><microglial cell><microgliocyte><model of animal><multidisciplinary><myelination><neonatal brain><neonatal chronic lung disease><neonatal lung injury><neonatal mice><neonatal pulmonary><neonate><neuronal><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><newborn chronic lung disease><newborn lung><newborn pulmonary><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oligos><ontogeny><pediatric><perivascular glial cell><pharmacologic><post-prematurity respiratory disease><premature><premature baby><premature infant human><prematurity><preterm baby><preterm infant><preterm infant human><preterm infants with chronic lung disease><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><randomized, clinical trials><resolutions><response><scRNA-seq><sham therapy><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><suprarenal gland><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptomics><two year old><two years of age><very premature><very preterm><vulnerable group><vulnerable individual><vulnerable people><youngster>