Carnaghan, Helen Kristina; (2018) Investigation of the Pathophysiology and In-Utero Treatment of Gastroschisis-Related Intestinal Dysfunction. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text Carnaghan_10064318_thesis.pdf Download (14MB) | Preview

Abstract

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 carboxypeptidase-like protein (ACLP) knockout mouse showed the AWD was not characteristic of gastroschisis as the externalised bowel was free floating within exocoelomic fluid and not the amniotic fluid. Bowel wall ICC were architecturally normal but reduced in number in AWD fetuses compared to controls. In-utero injection of IL-8 further reduced ICC numbers. In contrast, analysis of human pathological gut tissue showed no difference in the number or architecture of bowel wall ICC between gastroschisis and control tissue. However, the gastroschisis bowel wall was significantly thicker than that of controls with evidence of smooth muscle hyperplasia and deficiency of α-smooth muscle actin within the longitudinal muscle layer. The clinical retrospective data showed that early delivery of gastroschisis fetuses did not improve bowel function and was associated with prolonged time to full enteral feeds and length of hospital stay. Additionally, there was no evidence that administration of maternal antenatal corticosteroids improved time to full enteral feeds or length of hospital stay in gastroschisis infants. CONCLUSION: Phenotypic analysis of abdominal wall defects in murine models is challenging. However, accurate delineation of the defect anatomy is essential to ensure appropriate result reporting and data analysis. The presented data suggests the ICC may be less important as the cause of GRID than originally expected. However, another potential cause for GRID is bowel wall thickening comprising of smooth muscle hyperplasia and possible bowel myopathy for which there are several hypothesised triggers. Additionally, the data presented in this thesis do not support early delivery of gastroschisis fetuses or the administration of maternal antenatal corticosteroids as methods to improve gastroschisis infant outcomes. The results of this thesis have generated some important findings and have highlighted a number of novel hypotheses for the trigger of GRID. Further research on the basis of these findings within an appropriate animal model and through prospective non-invasive human studies are required in order to develop a targeted antenatal therapy to improve gastroschisis infant bowel function and clinical outcomes.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as CSVXMLJSON

Archive Staff Only

View Item