The critical role of monocytes In transplant-related acute lung injury

Abstract

Lung transplantation remains the final option for patients with end-stage lung disease. A significant proportion will develop primary graft dysfunction acutely post implantation, severely impacting on their morbidity and mortality. A key role for marginated monocytes has been identified in several experimental models of lung injury. Whilst other inflammatory leukocytes have been implicated in the pathogenesis of lung ischaemia-reperfusion injury (and primary graft dysfunction), a specific role for vascular monocytes has not yet been fully investigated. We hypothesised that marginated lung monocytes played a critical role in the pathogenesis of lung ischaemia-reperfusion injury. Our overall aims were to: (a) develop, optimise and characterise a murine model of ischaemia-reperfusion, utilising the isolated perfused lung system, (b) elucidate the role of monocytes with liposomal-clodronate depletion and adoptive transfer, and (c) to identify and characterise monocytes in human lung transplant samples and correlate them to patient outcomes. The major findings of this work were that lung marginated monocytes are retained and activated following ischaemia-reperfusion injury, inducing inflammatory mediator release. Clodronate depletion of vascular monocytes resulted in reversal of the injury and abrogated mediator release. Moreover, vascular monocyte repletion (via adoptive transfer), reinstated the injury and inflammation originally observed. Analysis of human lung samples, flushed prior to implantation, also demonstrated significant monocyte retention and activation, which correlated with primary graft dysfunction, in a pilot study of transplant recipients. In summary, this study was able to confirm a critical role for marginated monocytes in lung ischaemia-reperfusion injury. A significant number were retained, and activated, in both murine and human lung samples despite considerable pulmonary flushing. This indicates a propensity for these monocytes to be transferred as ‘passenger’ cells to recipients, where they are capable of the propagation of lung inflammation and injury following transplantation.