A Pilot Case-Control Study Investigating the Role of Epigenetics in Pediatric Acute Respiratory Distress Syndrome

Abstract

Acute Respiratory Distress Syndrome (ARDS) is a highly lethal affliction of pulmonary edema and hypoxia commonly associated with trauma, sepsis, and shock. The prevalence and lethality of ARDS in children has motivated continued translational study aimed at further elucidating its pathophysiology. DNA methylation has emerged as a dynamic, epigenetic regulator of gene expression. Previous work has suggested the role of differential DNA methylation as a critical regulator of ARDS pathophysiology in adults; however, this has not yet been investigated in pediatric patients. Here, we report the results of a prospective pilot case-control study investigating potential epigenetic differences underlying pediatric ARDS (PARDS). In addition to investigating disease- and severity-associated differences in DNA methylation in critically ill children, we also assessed epigenetic age acceleration (EAA) and telomere length as biomarkers of cumulative cell stress and proliferative history. Although there were no disease-associated differentially methylated regions (DMRs) observed in whole blood or tracheal aspirate samples, we report six potential DMRs associated with PARDS illness severity. Additionally, we report that samples collected from critically ill children have undergone significant epigenetic age acceleration relative to samples collected from healthy children, and that this difference is not observed when comparing EAA between critically ill and healthy adults. Finally, we report that absolute telomere length (aTL) is significantly shorter in cells found in the tracheal aspirate of children with PARDS—potentially indicative of increased cellular proliferation or exposure to reactive oxygen species.