Lung transplantation remains the only therapy proven to prolong survival and improve quality of life in advanced lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). The median survival after transplantation is currently 5.3 years. Little is known about the importance and function of the lymphatic circulation after graft has been implanted and subjects develop acute and/or chronic rejection. A key question is whether post-transplantation lymphangiogenesis is beneficial (e.g. by promoting efficient inflammatory cell clearance) or detrimental (e.g. by promoting antigen presentation within draining lymph nodes and stimulating alloimmune responses). The role of the lymphatic circulation in lung allograft survival and function remains unclear. Vascular endothelial growth factor (VEGF)-C mutated at residue 156 (VEGF-C C156S) has been shown to induce lymphangiogenesis and not angiogenesis. Our preliminary data indicate that fully allogeneic murine lung grafts exhibit a decrease in the density of lymphatic vessels with acute rejection. Importantly, stimulating lymphangiogenesis after rejection has been established results in improved rejection. We hypothesize that treatment of recipient mice with VEGF-C C156S after rejection occurs will result in improved graft function by increasing clearance of pro-inflammatory pro-fibrotic molecules such as hyaluronan. To test the validity of these hypotheses, we propose the following specific aims:
Aim 1 : Will test the hypothesis that inducing lymphangiogenesis after established rejection will lead to decreased signs of graft rejection and improved lung function. Our working hypothesis is that VEGF-C C156S will induce lymphangiogenesis and lead to improved graft rejection and function. Our approach will include treatment of mouse transplant recipients with VEGF-C C156S, followed lung function (imaging and physiological parameters) and assess signs of rejection (histology, protein and RNA analyses).
Aim 2 : Will test the hypothesis that the induction of lymphangiogenesis will result in enhanced HA clearance that will lead to improved lung allograft function. Our preliminary data show that there is increased hyaluronan deposition in lung rejection. Our working hypothesis is that the induction of lymphangiogenesis will result in improved hyaluronan clearance resulting in improved lung allograft function. Our approach will include examining lung allograft hyaluronan content before and after induction of lymphangiogenesis. In addition, we will block hyaluronan clearance and assess the transplanted lung with imaging, lung physiology and histological studies. If successful, this research will provide new insights into the mechanisms underlying the influence of lymhangiogenesis on lung tissue and the role the lymphatic circulation plays in vivo in lung rejection. In addition, it will pave the way for the development of novel strategies to tret acute rejection in lung transplant recipients.

Public Health Relevance

Lung transplantation is the only therapy for advanced end stage lung disease. Acute rejection is still very common after lung transplantation and is a major risk factor for chronic rejection and loss of graft function. Little is known about the role the lymphatic vasculature plays in allograft function. This project addresses the hypothesis that stimulating lymphatic vessel formation after acute rejection would lead to an improved graft function and decreased rejection, opening the path towards novel therapeutic avenues.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-DKUS-D (57))
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Eu, Jerry Pc
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Brigham and Women's Hospital
United States
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