Finn, Adam; (1994) Neutrophil-endothelial adherence pathways in paediatric cardiopulmonary bypass. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Surgical correction of congenital cardiac defects often requires cardiopulmonary bypass (CPB) to maintain systemic perfusion, a procedure which still carries significant morbidity and occasional mortality particularly in small children. CPB induces an acute inflammatory state unique in that it is iatrogenic and planned, rendering it peculiarly amenable to study. New information about leukocyte adhesion to endothelium, associated endothelial injury, and the control of these events by inflammatory cytokines was applied to the study of these patients. A flow cytometric assay of surface adhesion molecule expression on circulating neutrophils was developed. The nature and timing of the inflammatory changes induced by CPB were examined in a group of paediatric patients. Consistent changes in circulating neutrophil concentrations, Interleukin-8 (IL8) a pro-inflammatory cytokine with specific effects on neutrophil function, soluble C5b-9 a product of complement activation, and elastase a proteolytic enzyme released by neutrophils were demonstrated in plasma but changes in neutrophil adhesion molecule expression were inconsistent. Changes in the same variables in human blood in a model of CPB and the effects of soluble complement receptor 1 (sCR1), a specific, potent inhibitor of complement activation were examined. A clear pattern of changes in neutrophil adhesion molecule expression emerged in this system. Although inhibition of complement activation and IL8 release was achieved, changes in neutrophil adhesion molecule expression and release of elastase were unaffected. An in vitro model of neutrophil-mediated endothelial injury, assessed immunohistochemically by staining cultured human endothelial cells, was adapted to allow flow cytometric quantitation of neutrophil adhesion and changes in expression of neutrophil adhesion molecules CD11b/CD18 and Leukocyte selectin. Lipopolysaccharide and the secretagogue formyl methionine leucine phenylalanine(fMLP) were used to create a spectrum of degrees of endothelial disruption. Neutrophil adhesion was shown to correlate with loss of endothelial heparan sulphate but not fibronectin. Neutrophil expression of CD11b/CD18 did not predict adhesion or endothelial injury. These studies may provide the basis for new anti-inflammatory therapeutic strategies.

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