Focusing on Donor Lung Organ Storage: Implications for Inflammation Post-Transplant

Abstract

Lung transplantation is a surgical option to replace a diseased lung with a healthy lung from a donor. This surgical process causes stop of blood flow from the point of organ retrieval or procurement followed by cold and warm storage phase (ischemia), followed by the re-instatement of blood flow with implantation (reperfusion) that occurs upon transplant. The injury incurred during ischemia (retrieval and storage) together with the injury from reperfusion (I/R injury) is considered as the main driver of onset of primary graft dysfunction (PGD). PGD is a multifactorial injury that is characterized by cellular infiltrates and severe oxidative damage; it occurs within 24 h post-transplant and is a critical factor in determining transplant outcome. PGD occurs in large part due to inflammation post-transplant when polymorphonuclear neutrophils (PMN) are recruited to and adhere to the endothelium of the lung, transmigrate and release reactive oxygen species (ROS). Recognizing the role of PMN in poor transplant outcome, the clinical strategy at present is to block PMN activation by a non-specific immunosuppression regimen administered to the transplant recipient.As immunosuppression therapy has severe side effects, alternate means of blocking and inhibiting inflammation in the lung are being considered. The binding of PMN to the endothelium is a prerequisite of inflammation; thus our research is focused on the endothelium of the donor lung so as to block endothelial signals that facilitate its bindingto PMN. Such a strategy of inhibiting the moieties on the vascular wall so that as prevent donor lung endothelial interaction with the recipient’s PMN is an early intervention and has the potential to prevent injury completely. In contrast, immunosuppression involves minimizing influx and recruitment of PMN and immune cells after the initial adherence and binding that would take place immediately upon transplant.

Our extensive work on lung storage or ischemia shows that the pulmonary endothelium responds to stop of blood flow by a signaling cascade that involves K_ATP channel closure, PI3Kinase activation and assembly of the enzyme NADPH oxidase 2 (NOX2) leading to the generation of ROS. We found that the ROS thus produced triggers the onset of an inflammation cascade during the storage period itself, ahead of the transplant event. Onset of inflammation causes damage to the donor lung during storage thus affecting donor lung availability; additionally it can potentially drive immune cell recruitment via inflamed lung vessel wall. Thus optimal storage conditions such as keeping the lung (organ) perfused or inhibiting ischemia induced signaling by blocking K_ATP closure, PI3K activation or NOX2 assembly may potentially preserve lung viability and minimize inflammation and injury post-transplant.