Investigation of the Pathophysiology and In-Utero Treatment of Gastroschisis-Related Intestinal Dysfunction

BACKGROUND: Gastroschisis is a paraumbilical abdominal wall defect through which the bowel herniates. The bowel is in direct contact with the amniotic fluid. At birth the bowel is often thickened and shortened. The main gastroschisis-related morbidity is that of intestinal dysmotility but the mechanism(s) underlying this are poorly understood and no treatment advances have occurred since the advent of parenteral nutrition. Human studies have shown that the third trimester amniotic fluid of gastroschisis pregnancies is proinflammatory. In addition, in animal models of gastroschisis and human pathological gut tissue interstitial cells of Cajal (ICC – pacemaker cells of the gut) have been found to be decreased in number and immature within gastroschisis bowel. HYPOTHESES: Gastroschisis-related intestinal dysfunction (GRID) is secondary to deficient, immature bowel wall ICC. AIMS: My primary aim in this thesis was to investigate the development of ICC in gastroschisis utilising genetic animal models and human pathological gut tissue. Additionally, I aimed to determine the overall morphology of gastroschisis bowel wall, the impact of inflammatory modulation on bowel wall development and the impact of clinical antenatal interventions on infant outcomes. METHODS: Quantitative analysis of bowel wall ICC, enteric neurons and architecture were performed utilising genetic animal gastroschisis models and human pathological tissue. Modulation of in-utero inflammation was performed through in-utero injections of IL-8 (pro-inflammatory protein) in a genetic animal gastroschisis model. Finally, retrospective clinical data on gastroschisis were collected from three paediatric surgical centres to determine whether early delivery or administration of maternal antenatal corticosteroids could improve infant morbidity. RESULTS: Phenotypic analysis of the Scribble knockout mouse model revealed the expressed abdominal wall defect (AWD) to be that of exomphalos rather than gastroschisis. Additionally, phenotypic analysis of the aortic ...