Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection
Ye Cui, … , Gary Visner, Souheil El-Chemaly
Ye Cui, … , Gary Visner, Souheil El-Chemaly
Published October 20, 2015
Citation Information: J Clin Invest. 2015;125(11):4255-4268. https://doi.org/10.1172/JCI79693.
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Research Article Angiogenesis Cardiology Inflammation Oncology Vascular biology

Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

Abstract

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes.

Authors

Ye Cui, Kaifeng Liu, Maria E. Monzon-Medina, Robert F. Padera, Hao Wang, Gautam George, Demet Toprak, Elie Abdelnour, Emmanuel D’Agostino, Hilary J. Goldberg, Mark A. Perrella, Rosanna Malbran Forteza, Ivan O. Rosas, Gary Visner, Souheil El-Chemaly

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Figure 8

Decreased HA accumulation in treated human lung allografts correlates with improved functional outcome.

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Decreased HA accumulation in treated human lung allografts correlates wi...
(A) Left panel: representative images of paired HABP fluorescence staining (red) of human lung sections before and after treatment for acute lung rejection. Nuclei were counterstained with DAPI (blue). Right panel: quantification of HABP IOD. (B) FEV1 was measured before and after treatment for acute lung rejection. (C) Representative images of paired D2-40 immunostaining (indicated by black arrows) of human lung sections before and after treatment for acute lung rejection (left panels) and quantification of D2-40–positive lymphatic vessel density (right panel). Scale bars: 500 μm (A), 200 μm (C). *P < 0.05, **P < 0.01, as determined by paired 2-tailed Student’s t test (n = 5 patients/group).