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Title: Musocal protection during human foetal gastrointestinal tract ontogeny and in neonatal intestine in health and disease
Author: Vieten, Daniela
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Background Necrotising enterocolitis (NEe) remains a leading cause of mortality in neonatal intensive care units. There is currently a poor understanding of the molecular mechanisms underlying the pathogenesis of NEC and a lack of effective treatment strategies. Studies performed by various groups suggest that intestinal barrier failure plays a critical role in the development of NEC. The intestinal mucosal barrier is a complex defence system against the onslaught of noxious substances within the lumen, while allowing the influx of nutrients. Mucin glycoproteins and trefoil factor family (TFF) peptides are major components of the mucus gel layer lining the gastrointestinal tract (GIT) and they play pivotal roles in normal intestinal homeostasis and in the protection and repair of the GI epithelium following mucosal injury. Aims The aim of this thesis is to elucidate developmental changes in the composition of the intestinal mucus barrier during foetal GIT ontogeny and to examine alterations in GI mucosal protection and repair in acute NEC that may be implicated in the pathogenesis of the disease. Results Alterations in mucin and trefoil gene and protein expression and in mucin 0- acetylation were detected in the foetal GIT by RTPCR, in situ hybridisation and immunohistochemistry, when compared to normal neonatal bowel. Subtle differences were detected in mucin expression in normal neonatal bowel when compared to reports in the literature of findings in adult bowel. Mucin and trefoil gene and protein expression were significantly altered in acute NEC when compared to nannat neonatal bowel and there were significant changes in the patterns of sialylation and O-acetylation. The ulcer-associated cell linage (UACL) was not induced by NEC, ectopic TFF1 expression from neuroendocrine cells was however detected in acute NEC and in the recovery phase. Conclusion Significant differences were seen in the expression of components of the mucosal defence barrier in foetal bowel when compared to normal neonatal controls . Immature expression of proteins involved in mucosal protection following premature birth is unlikely to be a primary cause of NEC but may contribute to the pathogenesis. Mucin gene and protein expression were largely preserved in NEC but significant changes were noted in posttranslational glycosylation. There was an impaired TFF peptide response in the immature neonatal bowel in response to mucosal injury in acute NEe. The observed alterations in mucosal defence proteins are likely to be a consequence of NEC rather than the primary cause but they may contribute to the severe necrosis and tissue loss observed in the GIT of infants with NEC. This thesis demonstrates that the proliferative response, although present, was insufficient to rapidly reverse the mucosal insult observed in NEC. More research is required in order to be able to exploit the potential therapeutic value of factors that enhance mucosal protection , restitution and regeneration.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available