Title:
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The Mechanisms of Capillary Leak in Meningococcaemia
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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.
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