Image from left to right: Drs. Noda, Sanchez, and Gerlach
Pablo G. Sanchez, MD, PhD, McGowan affiliated faculty and Chief, Division of Lung Transplant and Lung Failure in the Department of Cardiothoracic Surgery at the University of Pittsburgh, as well as Brack G. Hattler Professor in Cardiothoracic Transplantation, and Jörg C. Gerlach, MD, PhD, Director of the interdisciplinary Biorector Group at the McGowan Institute, are the Principal Investigators (PIs) on a new R21 award from the National Heart, Lung, and Blood Institute. Kentaro Noda, PhD, Research Program Manager of Ex Vivo Lung Perfusion in the Department of Cardiothoracic Surgery at the University of Pittsburgh is also part of the project.
The project, titled “Incorporating hepatic cell function into lung ex vivo lung perfusion for transplant preservation” spans from April 2023 to January 2025.
The project aims “to provide proof-of-principle for the ability of hepatocyte BRx to enhance lung graft preservation.” Lung graft preservation, conducted with static cold storage, is limited to 8 hours or less. The longer an organ remains in cold storage, the chances of primary graft dysfunction increases.
According to the project abstract:
[P]rimary graft dysfunction is a risk factor for developing chronic rejection, which could account for the low 5-year survival rate (50%) following lung transplantation (LTx). Ex Vivo Lung Perfusion (EVLP) is expected to improve lung preservation and transplant outcomes by providing normothermic circulation and ventilation. A problem is that current EVLP is self-limited by normothermia-activated lung metabolism. The accumulation of toxic metabolites leads to a proinflammatory state, activating Receptor of Advanced Glycation End-Products (RAGE) and nuclear factor (NF)-kB mechanisms, which in turn upregulate proinflammatory cytokine signaling. […] In previous work, we have maintained normal hepatic detoxification, synthesis, and regulation in in vitro circuits using liver cell bioreactors (BRx). […] We will incorporate a hepatic BRx in our established EVLP circuits and demonstrate its effect on short-term LTx in experimental rat models. We will repeat these experiments using a cadaveric human EVLP model. We will conduct comprehensive phenotypic, transcriptional, and functional endpoint assessments on lung tissue and hepatic cells in BRx, such as RAGE and NF-kB.
The project seeks to change the current state of EVLP for lung preservation in order to permit lungs to be preserved for longer periods of time outside of the donor body with less damage to the organ. This equates to increasing viable donor organ transportation time and distance, improving lung transplant wait lists, and ultimately improving post-transplant patient survival.