Pathogenesis of Bronchopulmonary Dysplasia: An Unanticipated Journey

Abstract

The problemRespiratory failure and mechanical ventilation (RFMV) predispose preterm babies toward bronchopulmonary dysplasia (BPD also called neonatal chronic lung disease). MV is necessary to keep many preterm babies with RF alive. Therefore, MV is life‐saving. But MV has collateral consequences, including short and long‐term impairments of outcomes for lung function, cardiovascular function, neurodevelopment, kidney function, and nutrition and growth. Mechanisms by which impairments occur are not known and therapies are not available.CostsPreterm birth and the consequences of RFMV lead to societal, family, and survivor costs that are staggering. For example, 85% of medical care services for infancy are delivered to the tiniest (<1000 gm) babies. Yearly, ~50,000 of newborn babies in the US are at high‐risk. In 2005, annual societal economic burden associated with premature babies was ~$26 billion, or ~$52,000/infant born preterm.An unanticipated journeyThe start of my scientific career was not aimed at BPD. My first grant award and publication, while an undergraduate student at Lawrence University, focused on developmental botany. My graduate training at Loyola University of Chicago, Stritch School of Medicine focused on the renal lymphatic system. My postdoctoral fellowship training at UCSF's Cardiovascular Research Institute, and the next eleven years as junior faculty at several east coast universities, focused on acute respiratory distress syndrome. Unbeknownst to me, my future colleague, who trained a decade earlier in the same lab at UCSF as I and who remained there, albeit in Pediatrics clinically caring for and studying preterm infants, was following my career progression. I learned in 1990 of his move to the University of Utah to establish a model of BPD and that I was to join him in the endeavor. My unanticipated journey began.Preterm lamb model of BPDThree of us developed the unique chronic preterm lamb model of BPD. Not an easy feat! Our first paper was published in 1997. After my colleagues subsequently left the University of Utah, I moved the model to new questions and wider breadth. A major effort was to strategically craft a team to provide expertise across disciplines that contribute to clinical care of preterm babies with RFMV, radiological assessment of their brain, prediction whether neurodevelopmental impairment will persist later in life, and testing pathogenic mechanisms.Our approach to mechanismOur idea is that a common mechanism integrates the pathogenesis of BPD and its co‐morbidities during RFMV and later in life. The common mechanism is epigenetics (epigenetics as a dynamic regulator of gene expression through alterations in chromatin structure and DNA methylation, without altering DNA sequence).Training the next generationsAnother unanticipated outcome is unparalleled training of young scientists. To date, nearly 250 trainees have spent 2 to 6 years tending lambs and completing research projects. The majority are undergraduate students or medical students, ~85% of whom graduated to the professional training of their choice.OutcomesResults from our studies are contributing to identification of pathogenic mechanisms that underlie BPD. Two current projects hold the potential of being treatments for BPD and its long‐term consequences.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.