Necrotising enterocolitis (NEC) is an acute inflammatory condition of the preterm intestine associated with significant morbidity and mortality. The pathogenesis remains unclear. The Protein C (PC) pathway is the main anticoagulant system of the body with key anti-‐ inflammatory, anti-‐apoptotic and barrier stabilising effects on the microcirculation, cells of the innate immune system and epithelial cells of the lungs, intestine and skin. Neonates, and preterm neonates in particular, have a physiological deficiency in the PC pathway. This thesis was aimed at discovering the effects of NEC on the PC pathway. We demonstrated with immunohistochemistry that thrombomodulin (TM) and endothelial protein C receptor (EPCR) are strongly expressed in healthy preterm neonatal bowel; these receptors are the activation apparatus of PC. On examination of intestine affected by NEC, we discovered TM and EPCR expression was reciprocally reduced with increasing inflammation, but lost only in necrotic areas. Dual staining showed that intravascular deposits of fibrin occurred in vessels with weak or absent TM expression. The effect of NEC on the concentrations PC pathway proteins was assessed in an observational study. We report for the first time that activated protein C (APC) levels in healthy preterm infants are low; in keeping with the physiologically low levels of PC. In NEC the levels of PC, free and total PS are reduced. The levels of APC varied; some infants were able to boost levels 10-‐fold while others remained unchanged. We studied the effect of APC and PC supplementation in an animal model of bowel ischaemia-‐reperfusion injury designed to simulate prophylaxis and treatment schedules. APC given after reperfusion reduced intestinal injury; PC had less effect. The results presented in this thesis show that PC pathway activity is reduced in NEC and may contribute to the pathogenesis of the condition; introducing the possibility of new therapeutic options.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626215 |
| Date | January 2013 |
| Creators | Lister, P. H. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1396238/ |
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