The objective of this study is to provide further evidence that corneal lymphangiogenesis occurs after keratoplasty, and to explore the association of corneal hemangiogenesis, corneal inflammation and transplantation history with corneal lymphangiogenesis. Rat corneal lymphangiogenesis was examined by electron microscopy, lymphatic vessel endothelial receptor (LYVE-1) immunohistochemistry, and whole-mount immunofluorescence at 1, 3, 7, 10 and 14 days after corneal transplantation. Blood and lymphatic vessels in human transplanted corneas were identified by LYVE-1 and CD31 immunohistochemistry, then the association between corneal blood vessel counting, inflammatory index and transplantation history with the lymphatic vessel counting was examined.The results showed that corneal lymphangiogenesis was present in all rat corneas and 26% of human transplanted corneas. Lymphatic vessel counting was significantly associated with blood vessel counting, inflammatory index and transplantation history (all p values <0.0001). We conclude that corneal lymphangiogenesis develops after keratoplasty, and is strongly associated with hemangiogenesis, inflammation and the history of transplantation.

Ormerod LD, Abelson MB, Kenyon KR: Standard models of corneal injury using alkali-immersed filter discs. Invest Ophthalmol Vis Sci 1989;30:2148–2153.
Streilein JW, Yamada J, Dana MR, Ksander BR: Anterior chamber-associated immune deviation, ocular immune privilege, and orthotopic corneal allografts. Transplant Proc 1999;31:1472–1475.
Cursiefen C, Kuchle M, Naumann GO: Angiogenesis in corneal diseases: histopathology of 254 human corneal buttons with neovascularization. Cornea 1998;17:611–613.
Yamagami S, Dana MR: The critical role of lymph nodes in corneal alloimmunization and graft rejection. Invest Ophthalmol Vis Sci 2001;42:1293–1298.
Yamagami S, Dana MR, Tsuru T: Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk corneal transplantation. Cornea 2002;21:405–409.
Cursiefen C, Cao J, Chen L, Liu Y, Maruyana K, Jackon D, Kruse FE, Wiegand SJ, Dana MR, Streilein JW: Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest Ophthalmol Vis Sci 2004;45:2666–2673.
Ling S, Qing X, Hu Y: Lymphangiogenesis occurring in transplanted corneas. J Huazhong Univ Sci Technolog Med Sci 2006;26:241–244.
Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, Van Rooijen N, Takenaka H, D’Amore PA, Stein-Streilein J, Losordo DW, Streilein JW: Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 2005;115:2363–2372.
Cursiefen C, Chen L, Dana MR, Streilein JW: Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology (review). Cornea 2003;22:273–281.
Cursiefen C, Schlotzer-Schrehardt U, Kuchle M, et al: Lymphatic vessels in vascularized human corneas: immunohistochemical investigation using LYVE-1 and podoplanin. Invest Ophthalmol Vis Sci 2002;43:2127–2135.
Williams KA, Coster DJ: Penetrating corneal transplantation in the inbred rat: a new model. Invest Ophthalmol Vis Sci 1985;26:23–30.
Laria C, Alio JL, Ruiz-Moreno JM: Combined non-steroidal therapy in experimental corneal injury. Ophthalmic Res 1997;29:145–153.
Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, Cao Y: PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 2004;6:333–345.
Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y: Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 2005;102:15593–15598.
Bono P, Wasenius VM, Heikkila P, Lundin J, Jackson DG, Joensuu H: High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer. Clin Cancer Res 2004;10:7144–7149.
Banerji S, Ni J, Wang S, Clasper S, Su J, Tammi R, Jones M, Jackson DG: LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 1999;144:789–801.
Jackson DG: Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis (review). APMIS 2004;112:526–538.
Chang LK, Garcia-Cardena G, Farnebo F, Fannan M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A: Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 2004;101:11658–11663.
Mouta C, Heroult M: Inflammatory triggers of lymphangiogenesis (review). Lymphat Res Biol 2003;1:201–218.
Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K: Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 2000;156:1499–1504.
Witmer AN, van Blijswijk, Dai J, Hofman P, Partanen TA, Vrensen GF: VEGFR-3 in adult angiogenesis. J Pathol 2001;195:490–497.
Mimura T, Amano S, Usui T, Kaji Y, Oshika T, Ishii Y: Expression of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in corneal lymphangiogenesis. Exp Eye Res 2001;72:71–78.
Cursiefen C, Hofmann-Rummelt C, Kuchle M, et al: Pericyte recruitment in human corneal angiogenesis: an ultrastructural study with clinicopathological correlation. Br J Ophthalmol 2003;87:101–106.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.