The immunological impact of lung ventilation during cardiopulmonary bypass

Abstract

Cardiopulmonary bypass (CPB) is associated with postoperative pulmonary dysfunction, predisposing patients to considerable morbidity and mortality. The association of CPB with pulmonary dysfunction is thought to be driven by the development of a systemic inflammatory response which is characterised by neutrophil dysregulation and inflammatory cytokine release. Emerging evidence suggests that the human lung may play a beneficial role in modulating circulating neutrophil function thus potentially preventing organ dysfunction which is driven by neutrophil dysregulation. This thesis describes novel work using a one-lung ventilation model with direct pulmonary vein blood sampling in patients undergoing coronary artery bypass (CABG) surgery to explore the effects of ventilation on the innate immune system with focus on circulating neutrophil function and cytokine release. Adult patients awaiting ‘on-pump’ CABG surgery were recruited to two separate cohorts which differed in the intensity of one-lung ventilation to test our hypothesis that ventilation during CPB has beneficial immunomodulatory effects. Five blood samples were obtained from each patient during the operation: three central venous samples and one sample from both the left and right pulmonary veins. CPB had no apparent effect on the phagocytic function or priming status of circulating neutrophils however there was an increase in pro-inflammatory and anti-inflammatory cytokine concentrations in the post-CPB blood samples. Lung ventilation during cardiopulmonary bypass did not impact upon pulmonary blood neutrophil phagocytosis or priming status, nor did it alter postoperative plasma cytokine levels. These results suggest that lung ventilation during cardiopulmonary bypass has no apparent immunomodulatory benefit and that other therapeutic strategies to prevent post-CPB organ dysfunction should be explored. A second smaller laboratory study was undertaken alongside the clinical study which explored the effects of recombinant human interferon gamma (IFNγ) on the phagocytic function of neutrophils. Using an in vitro model, phagocytic function of neutrophils from healthy volunteers was impaired by pre-incubation with the β2-agonist, salbutamol. This model was then used to explore the effect of IFNγ on the ability to restore phagocytic function and the downstream cell signalling pathways involved in neutrophil phagocytosis. IFNγ restored v phagocytosis of neutrophils pre-incubated with salbutamol and appeared to facilitate this by restoring RhoA activity, a key component of complement mediated phagocytosis. Moreover, Jak1, Jak2 and Stat1 all appeared to be important components of the cell signalling pathway involved in IFNγ-mediated restoration of neutrophil phagocytosis. This work suggests that there is a potential therapeutic role for IFNγ in patients with impaired neutrophil phagocytosis such as that induced by severe sepsis and provides a platform for further exploration of the downstream cell signalling pathways involved