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가톨릭관동대학교 의과대학

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Ocul. Surf., Volume 22, October 2021, Pages 72-79 | https://doi.org/10.1016/j.jtos.2021.07.003 Corneal lymphangiogenesis in dry eye disease is regulated by substance P/neurokinin-1 receptor system through controlling expression of vascular endothelial growth factor receptor 3

Seok Jae Lee^a,b,1, Sang-Taek Im^a,1, Jun Wu^a,b, Chang Sik Cho^a, Dong Hyun Jo^c, Yihe Chen^d,e, Reza Dana^d,e, Jeong Hun Kim^a,b,f,g,**, Sang-Mok Lee^h,i,*

^a Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea ^b Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea ^cDepartment of Anatomy & Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea ^d Schepens Eye Research Institute of Massachusetts Eye and Ear, MA, USA ^e Department of Ophthalmology, Harvard Medical School, Boston, MA, USA ^f Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Republic of Korea ^g Advanced Biomedical Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea ^h Department of Cornea, External Disease & Refractive Surgery, HanGil Eye Hospital, Incheon, Republic of Korea ⁱ Department of Ophthalmology, Catholic Kwandong University College of Medicine, Gangneung-si, Republic of Korea

¹These authors contributed equally to this work.

^*Corresponding author.

Abstract

Purpose
To evaluate the role of substance P (SP)/neurokinin-1 receptor (NK1R) system in the regulation of pathologic corneal lymphangiogenesis in dry eye disease (DED).

Methods
Immunocytochemistry, angiogenesis assay, and Western blot analysis of human dermal lymphatic endothelial cells (HDLECs) were conducted to assess the involvement of SP/NK1R system in lymphangiogenesis. DED was induced in wild-type C57BL/6 J mice using controlled-environment chamber without scopolamine. Immunohistochemistry, corneal fluorescein staining, and phenol red thread test were used to evaluate the effect of SP signaling blockade in the corneal lymphangiogenesis. The expression of lymphangiogenic factors in the corneal and conjunctival tissues of DED mouse model was quantified by real-time polymerase chain reaction.

Results
NK1R expression and pro-lymphangiogenic property of SP/NK1R system in HDLECs were confirmed by Western blot analysis and angiogenesis assay. Blockade of SP signaling with L733,060, an antagonist of NK1R, or NK1R-targeted siRNA significantly inhibited lymphangiogenesis and expression of vascular endothelial growth factor (VEGF) receptor 3 stimulated by SP in HDLECs. NK1R antagonist also suppressed pathological corneal lymphangiogenesis and ameliorated the clinical signs of dry eye in vivo. Furthermore, NK1R antagonist effectively suppressed the lymphangiogenic factors, including VEGF-C, VEGF-D, and VEGF receptor 3 in the corneal and conjunctival tissues of DED.

Conclusions
SP/NK1R system promotes lymphangiogenesis in vitro and NK1R antagonism suppresses pathologic corneal lymphangiogenesis in DED in vivo.

논문정보

형식Research article
게재일2021년 10월 (BRIC 등록일 2021-12-10)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

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