Lung Transplantation: Ischemia-Reperfusion Injury

Background

The yearly number of transplants worldwide has increased 130-fold over the last twenty years. Despite advances in surgical management, critical care, and immuno-suppression, long-term survival has not improved. In fact, outcomes for lung transplantation are the worst of any solid organ transplant. In most series, 30-day mortality rates are near 15%, and ~50% of lung transplant patients die within five years.

Lung ischemia-reperfusion (IR) injury following transplantation continues to be a common and significant cause of morbidity and mortality in the early postoperative period, with rates as high as 41% reported. The 30-day mortality of patients with IR injury is about 40% compared to 7% in patients without. Patients with IR injury demonstrate immediate impairment in lung function after transplant accompanied by pulmonary edema, increased pulmonary vascular resistance, and decreased airway compliance. Patients with IR injury require prolonged mechanical ventilation, longer hospital stays, and are at an increased risk of multi-organ failure.

Lung IR injury has long-term consequences as well, where IR injury is also a risk factor for late graft rejection (bronchiolitis obliterans). Treatment strategies for patients that develop IR injury consist primarily of maintaining oxygenation and lung function. Use of inhaled nitric oxide has offered only limited benefit. IR injury occasionally is so severe that extracorporeal membrane oxygenation is required to maintain oxygenation. Clearly, prevention of IR injury is sorely needed in the area of lung transplantation, and studies in our laboratory address both causes and prevention of IR injury.

Basic Science Model

In our lab, we utilize four models of pulmonary function following ischemia and reperfusion: 1) an isolated, blood perfused, ventilated rabbit lung model, 2) a porcine left lung transplant model, 3) an in vivo, left hilar clamp model in mice, and 4) a rat model of cardiopulmonary bypass. Typically, we use our small rodent models for initial studies to help establish and screen specific pathways and targets. Our clinically relevant in vivo porcine lung transplantation model is used to confirm results found in the rodent models as well as to test pre-clinical therapies. In addition to these animal models, we also utilize an in vitro model to study the effects of IR on transformed and primary pulmonary cells such as epithelial cells, macrophages, T cells, and dendritic cells.

Some areas IR injury currently under investigation in our lab include 1) the role of adenosine receptors, 2) the role of T cells, dendritic cells and IL-17/IL-23 production, 3) the role of NADPH oxidase-dependent generation of reactive oxygen species, and 4) the role of alveolar epithelial cells and their crosstalk with other pulmonary cells such as macrophages and T cells.

More information on our IR research can be found on our TCV Surgery Research Projects website.