Don Yuen1, Bronek Pytowski, Lu Chen. 1. Center of Eye Disease and Development, Program in Vision Science, and School of Optometry, University of California, Berkeley, CA 94720, USA.
Abstract
PURPOSE: Lymphangiogenesis (LG) accompanies many corneal diseases after inflammatory, infectious, or chemical insults and is a primary mediator of transplant rejection. The purpose of this study was to investigate whether there is a time window for therapeutic intervention of corneal LG and whether a combined blockade of VEGFR-2 and VEGFR-3 effectively suppresses early-, middle-, or late-stage LG. METHODS: Corneal inflammatory neovascularization was induced by a standard suture placement model in mice. Neutralizing antibodies against VEGFR-3 and/or VEGFR-2 were administrated systemically with the treatment started at postoperative day 0, day 7, or day 14. Whole mount corneas were sampled for immunofluorescence microscopic studies using LYVE-1 (a lymphatic marker) antibodies. Digital images were analyzed by software. RESULTS: Both VEGFR-3 and VEGFR-2 were involved in corneal suture-induced inflammatory LG. Their combined blockade led to a significant inhibition of both early- and middle-stage LG while demonstrating no effect on late-stage LG. CONCLUSIONS: Corneal inflammatory LG has a discrete time window for intervention therapy. Although it is important to start the treatment as soon as possible, interventions initiated in the middle of the LG process are still effective. These novel findings will shed some light on our understanding of inflammatory LG and the development of new therapeutic protocols for LG-related diseases at different stages.
PURPOSE: Lymphangiogenesis (LG) accompanies many corneal diseases after inflammatory, infectious, or chemical insults and is a primary mediator of transplant rejection. The purpose of this study was to investigate whether there is a time window for therapeutic intervention of corneal LG and whether a combined blockade of VEGFR-2 and VEGFR-3 effectively suppresses early-, middle-, or late-stage LG. METHODS: Corneal inflammatory neovascularization was induced by a standard suture placement model in mice. Neutralizing antibodies against VEGFR-3 and/or VEGFR-2 were administrated systemically with the treatment started at postoperative day 0, day 7, or day 14. Whole mount corneas were sampled for immunofluorescence microscopic studies using LYVE-1 (a lymphatic marker) antibodies. Digital images were analyzed by software. RESULTS: Both VEGFR-3 and VEGFR-2 were involved in corneal suture-induced inflammatory LG. Their combined blockade led to a significant inhibition of both early- and middle-stage LG while demonstrating no effect on late-stage LG. CONCLUSIONS: Corneal inflammatory LG has a discrete time window for intervention therapy. Although it is important to start the treatment as soon as possible, interventions initiated in the middle of the LG process are still effective. These novel findings will shed some light on our understanding of inflammatory LG and the development of new therapeutic protocols for LG-related diseases at different stages.
Authors: Tina Dietrich; Felix Bock; Don Yuen; Deniz Hos; Björn O Bachmann; Grit Zahn; Stanley Wiegand; Lu Chen; Claus Cursiefen Journal: J Immunol Date: 2009-12-16 Impact factor: 5.422
Authors: Romulo J C Albuquerque; Takahiko Hayashi; Won Gil Cho; Mark E Kleinman; Sami Dridi; Atsunobu Takeda; Judit Z Baffi; Kiyoshi Yamada; Hiroki Kaneko; Martha G Green; Joe Chappell; Jörg Wilting; Herbert A Weich; Satoru Yamagami; Shiro Amano; Nobuhisa Mizuki; Jonathan S Alexander; Martha L Peterson; Rolf A Brekken; Masanori Hirashima; Seema Capoor; Tomohiko Usui; Balamurali K Ambati; Jayakrishna Ambati Journal: Nat Med Date: 2009-08-09 Impact factor: 53.440
Authors: Martin Michael Peter Schulz; Felix Reisen; Silvana Zgraggen; Stephanie Fischer; Don Yuen; Gyeong Jin Kang; Lu Chen; Gisbert Schneider; Michael Detmar Journal: Proc Natl Acad Sci U S A Date: 2012-09-04 Impact factor: 11.205
Authors: Don Yuen; Sammy Grimaldo; Roberto Sessa; Tatiana Ecoiffier; Tan Truong; Eric Huang; Michael Bernas; Sarah Daley; Marlys Witte; Lu Chen Journal: Invest Ophthalmol Vis Sci Date: 2014-04-29 Impact factor: 4.799