Meningococcal infection is a major infective cause of death in children and young people. Central to the underlying pathophysiological disturbances that occur in the course of invasive disease is a profound alteration in endothelial function giving rise to capillary leak, which is associated with high morbidity and mortality. The endothelium has an important role in maintaining the balance between intraluminal contents and the surrounding interstitial tissues. The key tenet in this thesis is that there is an increase in endothelial permeability in meningococcal disease, leading to hypovolaemia and tissue oedema. A central component of the capillary leak is the movement of colloidal proteins across the capillary wall. Albumin, a negatively charged protein, is the most important colloidal protein and is the protein predominantly involved. The hypothesis in this thesis is that albumin movement across the capillary wall relates to loss of negative charge on the endothelial surface (i.e. loss of electrostatic repulsion). As albumin moves out of the circulation, fluid and electrolyte movement occurs into interstitial tissues due to alteration in the osmotic forces that normally retain fluid within the vascular space, so contributing to capillary leak. The biochemical features of commercially available human, bovine and rabbit albumins were found to comprise a monomer, dimer and trimer. Rabbit serum albumin (fatty acid form), (RSA FFA) was labelled with a fluorescent marker Texas Red (TR), making the protein slightly negatively charged but otherwise unaltered biochemically. The TR labelled protein was made slightly more positive by methylation. Again the only difference from RSA was in charge. The clearances of these 2 protein probes were studied in healthy rabbits, with methylated albumin cleared faster from the circulation. In ventilated animals, the clearances of all the components of the labelled albumin were faster than in healthy animals, nonetheless the methylated albumin was still cleared faster. In ventilated shocked animals (by meningococcal lipopolysaccharide), there was no difference in the clearances of the 2 monomers, supporting the hypothesis. The dimers and trimers were handled differently to the monomers throughout. This work contributes to the idea that electrostatic forces have a role in shock.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:490815 |
| Date | January 2009 |
| Creators | Maconochie, Ian |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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