Neonatal colon exhibits enhanced post-ischemic repair relative to the neonatal jejunum

Abstract

Intestinal ischemia is the most common cause of gastrointestinal-related morbidity and mortality within the neonatal intensive care unit. Ischemia-induced loss of the intestinal epithelial barrier predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. Early barrier restoration relies on epithelial restitution to achieve wound closure, followed by rearrangement of tight junction proteins to re-establish barrier resistance. To inform putative therapeutics that promote rapid barrier repair in neonates, we have developed a highly-translational model of intestinal ischemia in the neonatal pig. Previous studies have demonstrated a significant defect in post-ischemic repair of the neonatal pig (2-weeks-old) jejunum relative to the juvenile (6-weeks-old) pig. Therefore, we hypothesized that the neonatal colon will demonstrate a similar defect in epithelial barrier repair. Segments of distal jejunum and spiral colon were subjected to surgically-induced ischemia followed by ex vivo recovery on Ussing chambers. Barrier repair was calculated by percent mucosal epithelialization, a measure of restitution, as well as transepithelial electrical resistance, a measure of barrier resistance. Unexpectedly, the ischemically-injured, ex vivo-recovered neonatal colon demonstrated significantly increased epithelial wound healing by restitution (p<0.005) as well as barrier resistance (p<0.05) relative to the neonatal jejunum. Furthermore, scanning electron microscopy revealed that colonocytes demonstrate a restitution phenotype defined by loss of their columnar morphology, marked flattening of their cellular profile and frequent formation of lamellipodia-like processes. Under identical experimental conditions, enterocytes do not demonstrate this phenotypic change. These findings suggest the presence of a colon-specific mechanism of intestinal epithelial barrier repair that is not present in the jejunum. Ongoing experiments aim to better elucidate the inter- and intracellular pathways that define this colon-specific mechanism of repair. Defining these pathways may inform the formulation of future pharmaceuticals that directly upregulate these pathways along the entire length of the intestine and therefore mitigate the effects of ischemic injury in neonates. NIH K01 OD 028207, NIH-NICHD R01 HD095876, U01 TR002953, T32OD011130 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.