Kurt H. Albertine, Ph.D., F.A.A.A., Professor of Pediatrics, Director of Basic and Translational Research Department of Pediatrics, Division of Neonatology
University of Utah School of Medicine
Salt Lake City, UT.
“Mechanical Ventilation Disrupts Long-Term Brain and Lung Outcomes for Former Preterm Lambs”
Acute respiratory failure of preterm human infants reflects immaturity of the lung following preterm birth, disrupted developmental processes, and dysregulated repair responses. Neonatal intensive care support for persistent respiratory failure leads to bronchopulmonary dysplasia (BPD, neonatal chronic lung disease). Gaps in knowledge about the underlying pathogenic mechanisms that contribute to BPD and its long-term outcomes are related, in part, to the challenge of establishing suitable animal models that include preterm birth and respiratory failure requiring prolonged invasive mechanical ventilation with oxygen-rich gas for days, weeks, or months. Our preterm lamb model provides unique opportunity for physiological studies of evolving disease pathogenesis that transitions to long-term outcomes. Our preterm lamb model is challenging because it requires intensive life-support care 24h per day for days or weeks. The arduous nature of these physiological studies is costly. Having two ventilation modes that provide either bad outcome (invasive mechanical ventilation) versus good outcome (non-invasive support) in the lung and brain is proving to be important for identifying pathogenic mechanisms. Our next assessment is epigenetic. Epigenetic regulation of gene expression uses modifications to chromatin, the unit of which is the nucleosome. Nucleosomes have 146 bp of DNA wrapped around an octomeric core of histone proteins. The modifications constitute an epigenetic code for regulation of gene expression by directing interactions between transcription complexes and promoters and transcription start sites along DNA. Epigenetic regulation of gene expression can use several mechanisms, including histone modifications, DNA methylation, microRNAs, and nucleosome positioning. Our first test is of histone modifications, in which we found that invasive mechanical ventilation leads to genome-wide histone hypoacetylation in the lung and brain compared to non-invasive support. Systemic daily treatment with histone deacetylase inhibitors preserved genome-wide histone acetylation and improved lung and brain outcomes acutely. Current studies are tracking outcomes longitudinally by sex as a biological variable to link early injury to long-term outcomes with epigenetic status.
Friday, December 8, 2017, 11:00AM-12:00PM, LIB-110
University of North Texas Health Science Center
Fort Worth, Texas