Lung transplantation (LTX) is a successful therapy that palliates patients with a variety of end stage lung diseases. Unfortunately, access to LTX is severely limited by a scarcity of suitable lungs from conventional organ donors. Thus, hundreds of LTX candidates die every year, and thousands of others are not even considered candidates. Donor lungs are far more scarce than any other solid organ for transplant. The "Lung-in-a-Box" project addresses this critical shortage by exploring an innovative approach that may be ideally and uniquely suited to the lung.
Among solid organs, the lung may be uniquely suited to retrieval for transplant after circulatory arrest, because the lung is the only solid organ transplanted that does not rely on perfusion for oxygen delivery and cellular respiration. Respiration for lung parenchymal cells occurs via air spaces, and perfusion of the pulmonary capillary bed represents an "oxygen steal". We have shown that lung tissue remains viable for substantial periods of time after circulatory arrest, in contrast to other solid organs. We have put forward the hypothesis that lungs may be suitable for transplant, even if recovered from donors hours after circulatory arrest and death. This hypothesis is supported by the observation that pulmonary epithelial cells can be cultured from morgue specimens and considerable experimental data.
Because lung tissue can remain viable for hours after circulatory arrest, lungs have been retrieved from non-heart beating donors (NHBDs) and transplanted successfully, in experimental animals and humans. The term NHBD refers to an individual who has sustained a cardiac arrest and has died, in the field or in an emergency room (ER). These individuals are generally not considered candidates for organ donation for transplant. It is unknown how many lungs might be suitable for transplant following recovery after circulatory arrest. Our long-term goal is the introduction of NHBDs in human lung transplantation so that the lung donor shortage could be eliminated.
Our Research Interests:
Our long-term goal is to establish a method to safely transplant lungs retrieved from NHBDs, to dramatically increase the lung donor pool. We have demonstrated the feasibility of LTX from NHBDs in dogs and rats. Lung transplantation from NHBDs is associated with lung ischemia-reperfusion injury (IRI). We identified altered expression in hundreds of genes after conventional LTX in humans and rats, and after LTX from NHBD donors in rats. Our central hypothesis -- that lung IRI can be modified to minimize effects on gas exchange and facilitate recovery of homeostasis of lungs from NHBDs -- will be tested by employing a variety of experimental models: 1) a cell culture model mimics the physical environment that the lung experiences during conventional transplant, and during simulated transplant from a NHBD. We hypothesize that endothelial and epithelial cells making up the alveolar wall may respond differently to the stresses associated with IRI. This model will allow for studies of response of the different cell types in lung tissue to simulated ischemia and reperfusion, and will facilitate studies of particular inhibitors of inflammation or blockade of specific signaling pathways on individual cell populations. 2) A murine (mouse) model of lung ischemia-reperfusion injury. This model will help determine the role of signal transduction pathways of gene expression contributing to lung IRI following transplant. The laboratory mouse is a potent tool for these studies because a variety of genetically manipulated strains are available, or can be bred, to shed light on the importance of specific activation pathways responsible for injury after ischemia and reperfusion. These studies will identify targets for pharmacologic or other types of intervention. 3) An ex-vivo rat lung perfusion and ventilation circuit followed by rat lung transplantation. This model will help determine the impact of modifying signal transduction pathways on post-transplant function of lungs retrieved from NHBDs. With this experimental work we seek to determine practical strategies to minimize ischemia-reperfusion injury in lungs retrieved from NHBDs, and thus dramatically increase the potential numbers of donor lungs for transplant.
(Click on the Diagram to see a Live Video of the ex-vivo circuit in action!)
To evaluate gas exchange function of lungs retrieved from human NHBDs, we have developed a modified cardiopulmonary bypass circuit, which is described in our web site lunginabag.net.
Click here to see a list of relevant publications we have authored
The International Society of Heart & Lung Transplantation
The Organ Procurement & Transplantation Network
United Network for Organ Sharing
Dr. Thomas M. Egan's Curriculum Vitae
for questions or feedback, e-mail Dr. Thomas Egan
if you are interested in supporting this research via a tax-deductible donation to the UNC Lung Transplant Research Fund, e-mail Anne Hager-Blunk or visit The Medical Foundation of North Carolina . To make a contribution on-line, please specify that your donation be directed to the UNC Lung Transplant Research Fund
for information regarding ex-vivo assessment of human lungs for transplant suitability, visit lunginabag.net