Zani, A; (2013) Investigation of Novel Therapeutic Agents for the Treatment of Necrotizing Enterocolitis. Doctoral thesis , UCL (University College London).

Abstract

Background/Aim: Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in neonates. The aim of this study was to: 1) establish and validate a neonatal rat model of NEC; 2) investigate the use of Captopril, an angiotensinconverting enzyme (ACE) inhibitor, in this model; 3) explore stem cells in this model as a new therapeutic strategy for NEC. Methods: 1) Various stress factors were employed to reproduce experimental NEC. Rats were assessed using old and new parameters of evaluation, including weight, survival, clinical conditions and behaviour, macroscopic and microscopic gut appearance. 2) Rats were administered Captopril and assessed for clinical status, body weight and survival rate. Resected intestine was evaluated for gut vessel dilatation and histology. 3) Rats intra-peritoneally injected with Amniotic Fluid Stem (AFS) cells and their controls were analysed for survival, gut macroscopic appearance and histology, immunofluorescence for AFS cell detection, bowel absorption and motility, degree of gut inflammation, and enterocyte apoptosis and proliferation. Results: 1) A neonatal rat model of NEC was established using hyperosmolar formula, hypoxia, and oral lipopolysaccharide. 2) Captopril reduced the severity of gut damage and the incidence of NEC via dilatation of the intestinal vasculature. 3) AFS cells integrated in the bowel wall and improved rat survival and clinical conditions, decreased NEC incidence and macroscopic gut damage, improved intestinal function, decreased bowel inflammation, increased enterocyte proliferation, and reduced apoptosis. The beneficial effect was achieved via modulation of stromal cells expressing COX-2 in the lamina propria, as shown by survival studies using selective and non-selective COX-2 inhibitors. Conclusions: In experimental NEC, both Captopril and AFS cells reduce the severity of intestinal damage and NEC incidence, ameliorating rat clinical conditions. However, AFS cells have the advantage of a powerful effect on mortality. Stem cell therapy may represent a new therapeutic option for infants with NEC.

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