Lung transplantation has become the mainstay of therapy for most end stage lung diseases including pulmonary emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis. However, increasing demand for suitable donor lungs far exceeds the number of available organs, in part because the lung is exquisitely sensitive to ischemia. Mild to severe ischemia-reperfusion injury is a frequent complication in lung transplant recipients. Current preservation fluids (e.g., low-potassium dextran glucose, LPDG) reliably preserve harvested lungs for 4 to 8hr and do not exploit recent advances in understanding of apoptosis to minimize lung injury during preservation. Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a pleiotropic growth factor that induces the activation and proliferation of diverse cell types, largely through its mitogenic and anti-apoptotic activities. Addition of recombinant SF/HGF to the preservation solution enhances post-transplant organ function. While administration of SF/HGF as protein therapy has potential for the treatment of lung dysfunction, its feasibility is limited by issues relating to inherent instability of proteins in solution and limited tissue half-life. Using a drug discovery engine that includes phage display, 3-dimensional molecular modeling, we have identified Refanalin, an organic small molecule SF/HGF mimetic that could serve as important therapeutics in ameliorating lung dysfunction and reducing early graft failure following transplantation. The objective of our study is to extend the lung preservation time up to 12-18 hr for lung transplantation using our lead SF/HGF mimetic as an additive to current preservation solutions. Preliminary data indicate that Refanalin protects against apoptotic/necrotic cell death in vitro and preserves organ function in vivo. In addition, Refanalin can improve success rate in liver and kidney transplantation in our animal models. The proposed work is designed to identify a strategy to determine the protective effects of Refanalin against ischemia-induced apoptosis/necrosis in lung transplantation in an animal model. Lung transplantation has become the mainstay of therapy for most end stage lung diseases including pulmonary emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis. A small- molecule drug that increases the preservation time of donor lungs will have tremendous clinical benefits. ? ? ?
