Program Director/Principal Investigator (Last, First, Middle): El-Chemaly, Souheil, Y Abstract 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 and Idiopathic Pulmonary Fibrosis. 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 detrimental (e.g. by promoting antigen presentation within draining lymph nodes and stimulating alloimmune responses) or beneficial (e.g. by promoting efficient inflammatory cell clearance). One key molecule is Hyaluronan (HA) which plays critical roles in lung injury and repair and importantly, HA plays a role in transplant rejection. The turnover of HA (several grams/day in humans) occurs primarily in the lymphatics that catabolize approximately 85% of HA. Lymphatic vessel endothelial HA receptor (LYVE-1) is an endocytic receptor for HA on the surface of lymphatic endothelial cells (LEC). In compelling published and preliminary data, we show that in mice recipient of an allogeneic lung graft there is a decrease in lymphatic vessels density in acute rejection. Importantly, stimulating lymphangiogenesis after rejection has been established resulted in improved rejection and lung allograft function. Importantly, the beneficial effects of induction of lymphangiogenesis were abrogated by co-treatment with LYVE-1 function blocking antibodies, suggesting important role(s) for LYVE-1 in inflammatory lung conditions. Based on these findings we propose as a guiding hypothesis that re-establishing the integrity of the lymphatic vasculature through donor lymphatic endothelial cells is critical for HA clearance and the resolution of acute lung rejection. Key corollaries are that targeting the lymphatic vasculature will have clinical efficacy in lung transplant; and that lymphatic-dependent molecules are detectable in the lung microenvironment and in sera of patients with acute lung rejection. To address our hypotheses, we propose these Specific Aims:
Aim 1 : To identify the origin of lymphatic endothelial cells in lymphatic vessel regeneration after lung transplantation. To determine mechanisms whereby lymphangiogenesis protects against lung allograft rejection.
Aim 3 : To demonstrate that lymphatic specific changes in lung tissue and peripheral blood can predict acute lung rejection and response to therapy. 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 treat acute rejection in lung transplant recipients. PHS 398/2590 (Rev. 06/09) Research strategy Page

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 by clearing molecules that are harmful to the graft. This will open the path towards novel therapeutic avenues.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Craig, Matt
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Cao, Severine; Courtwright, Andrew M; Lamattina, Anthony M et al. (2018) The impact of screening method on HLA antibody detection before and after lung transplantation: A prospective pilot study. J Heart Lung Transplant 37:531-533
Courtwright, Andrew; El-Chemaly, Souheil (2017) Broadening the investigation-short telomeres and lung transplantation outcomes in pulmonary fibrosis. J Heart Lung Transplant 36:833-834
Putman, Rachel K; Gudmundsson, Gunnar; Araki, Tetsuro et al. (2017) The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes. Eur Respir J 50:
Stump, Benjamin; Cui, Ye; Kidambi, Pranav et al. (2017) Lymphatic Changes in Respiratory Diseases: More than Just Remodeling of the Lung? Am J Respir Cell Mol Biol 57:272-279
Lama, Vibha N; Belperio, John A; Christie, Jason D et al. (2017) Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop. JCI Insight 2:
Cui, Ye; Steagall, Wendy K; Lamattina, Anthony M et al. (2017) Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation. Cancer Res 77:1492-1502
Cui, Ye; Liu, Kaifeng; Lamattina, Anthony Mark et al. (2017) Lymphatic Vessels: The Next Frontier in Lung Transplant. Ann Am Thorac Soc 14:S226-S232
Courtwright, Andrew M; Fried, Sabrina; Villalba, Julian A et al. (2016) Association of Donor and Recipient Telomere Length with Clinical Outcomes following Lung Transplantation. PLoS One 11:e0162409