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Lab Invest. 2014 Feb;94(2):150-60. doi: 10.1038/labinvest.2013.149. Epub 2013 Dec 23.

Intestinal epithelial apoptosis initiates gut mucosal injury during extracorporeal membrane oxygenation in the newborn piglet.

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  • 11] Division of Neonatology, Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA [2] Department of Pediatrics, Center for Neonatal and Pediatric Gastrointestinal Disease, University of Illinois at Chicago, Chicago, IL, USA.
  • 2Animal Resources Program, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 3University Hospital Services, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 4Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 5Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.
  • 61] Division of Neonatology, Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA [2] Department of Pediatrics, Center for Neonatal and Pediatric Gastrointestinal Disease, University of Illinois at Chicago, Chicago, IL, USA [3] Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.

Abstract

Neonates and young infants exposed to extracorporeal circulation during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass are at risk of developing a systemic inflammatory response syndrome with multi-organ dysfunction. We used a piglet model of ECMO to investigate the hypothesis that epithelial apoptosis is an early event that precedes villous damage during ECMO-related bowel injury. Healthy 3-week-old piglets were subjected to ECMO for up to 8 h. Epithelial apoptosis was measured in histopathological analysis, nuclear imaging, and terminal deoxynucleotidyl transferase dUTP nick end labeling. Plasma intestinal fatty acid-binding protein (I-FABP) levels were measured by enzyme immunoassay. Intestinal mast cells were isolated by fluorescence-assisted cell sorting. Cleaved caspase-8, caspase-9, phospho-p38 MAPK, and fas ligand expression were investigated by immunohistochemistry, western blots, and reverse transcriptase-quantitative PCR. Piglet ECMO was associated with increased gut epithelial apoptosis. Extensive apoptotic changes were noted on villus tips and in scattered crypt cells after 2 h of ECMO. After 8 h, the villi were denuded and apoptotic changes were evident in a majority of crypt cells. Increased circulating I-FABP levels, a marker of gut epithelial injury, showed that epithelial injury occurred during ECMO. We detected increased cleaved caspase-8, but not cleaved caspase-9, in epithelial cells indicating that the extrinsic apoptotic pathway was active. ECMO was associated with increased fas ligand expression in intestinal mast cells, which was induced through activation of the p38 mitogen-activated protein kinase. We conclude that epithelial apoptosis is an early event that initiates gut mucosal injury in a piglet model of ECMO.

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