Sultan, P; (2016) Molecular Mechanisms of Postoperative Lymphopenia. Doctoral thesis , UCL (University College London).

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Abstract

Low anaerobic threshold (AT), a marker of decreased exercise capacity, is associated with poorer outcomes following surgery. In this thesis I demonstrate a relationship between low preoperative AT and preoperative lymphopenia (low lymphocyte count). I subsequently demonstrate that preoperative lymphopenia is associated with prolonged hospitalisation and increased postoperative complications in 2 surgical cohorts (n=240 and n=881). Significant metabolic (bioenergetic) and functional changes occur in lymphocytes postoperatively, which may contribute to increased morbidity and mortality. Lymphocytes demonstrate a postoperative decrease in glycolysis and oxidative phosphorylation. Altered postoperative bioenergetic function are accompanied by an increase in mitochondrial reactive oxygen species production and a reduction in lymphocyte mitochondrial membrane potential, which are associated with apoptosis or cell death. Increased apoptosis of lymphocytes following surgery is the likely mechanism for acquired lymphopenia postoperatively (reduction in lymphocyte count which occurs postoperatively). A decrease in glycolysis is accompanied by increased CD8+ lymphocyte cytokine production. Postoperative inflammasome activation as demonstrated by increased caspase-1 activity, appears to occur secondary to glucocorticoid release associated with the stress response to surgery. Caspase-1 is associated with glycolysis inhibition (decreased glycolysis postoperatively) and increased apoptosis (reduced lymphocyte count postoperatively). Increased Interleukin-1-beta expression, which is associated with activation of the inflammasome and increased cytokine production, is demonstrated following incubation of lymphocytes with glucocorticoid. I hypothesise that postoperative changes in lymphocyte function occur secondary to increased glucocorticoid levels activating the inflammasome pathway during the stress response to surgery. This thesis provides translational data introducing the concept that lymphocyte metabolic abnormalities underlie the postoperative immune phenotype.

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