Allen, M.L.; (2004) Monocytes and their role in inflammation following cardiopulmonary bypass. Doctoral thesis , University of London.

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Abstract

Over the last decade there have been dramatic improvements in paediatric cardiac surgery and the outcome for children with congenital heart disease. Whilst the majority recover promptly from surgery, a small unpredictable group of children have persistant requirements for ventilatory and intensive care support. For these children sepsis and systemic inflammatory response syndrome (SIRS) appears to be a major causes of morbidity and mortality. Antigens of the major histocompatibility complex type II (MHC Class II) are decreased on circulating monocytes of many critically ill patients. Persistently low expression of these antigens has been associated with poor prognosis and increased susceptibility to infection. The work presented here examines the hypothesis that "monocyte deactivation", as indicated by reduced MHC Class II expression and decreased whole blood secretion of pro-inflammatory cytokines in response to lipopolysaccharide (LPS), is a factor in the development of sepsis/SIRS following cardiopulmonary bypass. Using flow cytometry, confocal microscopy, enzyme -linked immunosorbant assays, ex vivo whole blood stimulation, and real time-polymerase chain reaction it has been shown that (1) monocyte surface expression of MHC Class II falls following cardiac surgery involving CPB; (2) this reduction in surface expression is paralleled by a reduction in intracelleular MHC Class II stores, and increased transcription of MHC Class II related genes; (3) bypass results in the early and simultaneous rise in both pro-and anti-inflammatory cytokines; (4) whole blood drawn from patients following CPB is profoundly hyporesponsive to LPS stimulation; (5) whole blood hypo-responsiveness precedes the rise in circulating cytokine and that (6) the inflammatory response and morbidity following CPB may be influenced by the presence of cytokine polymorphisms. The results shown here strongly suggest that monocyte MHC Class II surface expression is an excellent diagnostic tool for the identification of the subgroup of children most likely to develop post-operative complications. By identifying this subgroup of children immunomodulative therapy can be appropriately targeted to restore homeostasis and improve outcome.

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