Lung Transplantation, Pulmonary Endothelial Inflammation, and Ex-Situ Lung Perfusion: A Review

Abstract

Lung transplantation (LTx) is the gold standard treatment for end-stage lung disease; however, waitlist mortality remains high due to a shortage of suitable donor lungs. Organ quality can be compromised by lung ischemic reperfusion injury (LIRI). LIRI causes pulmonary endothelial inflammation and may lead to primary graft dysfunction (PGD). PGD is a significant cause of morbidity and mortality post-LTx. Research into preservation strategies that decrease the risk of LIRI and PGD is needed, and ex-situ lung perfusion (ESLP) is the foremost technological advancement in this field. This review addresses three major topics in the field of LTx: first, we review the clinical manifestation of LIRI post-LTx; second, we discuss the pathophysiology of LIRI that leads to pulmonary endothelial inflammation and PGD; and third, we present the role of ESLP as a therapeutic vehicle to mitigate this physiologic insult, increase the rates of donor organ utilization, and improve patient outcomes.

Keywords: ex-situ lung perfusion; ischemic reperfusion injury; lung transplantation; primary graft dysfunction; pulmonary inflammation.

Figure 1

Factors and cellular mechanisms associated with lung ischemic reperfusion injury and primary graft dysfunction in lung transplantation. Risk Factors, RF; Cold Static Preservation, CSP; Reactive Oxygen Species, ROS; Adenosine Triphosphate, ATP; Interleukins, ILs; Damage Associated Molecular Patterns, DAMPs; Pulmonary Vascular Resistance, PVR; Lung Ischemic Reperfusion Injury, LIRI; Primary Graft Dysfunction, PGD; PaO₂/FiO₂ ratio, P/F ratio. Created with BioRender.com.

Figure 2

Custom-built NPV-ESLP platform: (A) Schematic of NPV-ESLP components; (B) Tevosol Inc. clinical trial prototype. (A) Oxygenated perfusate drains from the open left atrial system into a hard-shell reservoir (A), then through an arterial/particulate filter (D), pumped via the centrifugal pump (E) to the oxygenator/heat exchanger (F,G); which in turn warms the perfusate to normothermia (computer-controlled/adjusted (L)) and deoxygenates it with a sweep gas mixture (H,I). Prior to re-entering the lungs via the pulmonary arterial cannula (PA) for re-oxygenation, the perfusate passes by a flow probe sensor (J) and a pressure transducer (K). Negative Pressure Ventilation (NPV) circuit is depicted (B). An infusion pump (C) infuses insulin, dextrose, volume, and medications as needed.