title: Inhibition of vascular adhesion protein-1 suppresses endotoxin-induced uveitis.
abstract: Inflammatory leukocyte accumulation is a common feature of major ocular diseases, such as uveitis, diabetic retinopathy, and age-related macular degeneration. Vascular adhesion protein-1 (VAP-1), a cell surface and soluble molecule that possesses semicarbazide-sensitive amine oxidase (SSAO) activity, is involved in leukocyte recruitment. However, the expression of VAP-1 in the eye and its contribution to ocular inflammation are unknown. Here, we investigated the role of VAP-1 in an established model of ocular inflammation, the endotoxin-induced uveitis (EIU), using a novel and specific inhibitor. Our inhibitor has a half-maximal inhibitory concentration (IC(50)) of 0.007 microM against human and 0.008 microM against rat SSAO, while its IC(50) against the functionally related monoamine oxidase (MAO) -A and MAO-B is >10 microM. In the retina, VAP-1 was exclusively expressed in the vasculature, and its expression level was elevated during EIU. VAP-1 inhibition in EIU animals significantly suppressed leukocyte recruitment to the anterior chamber, vitreous, and retina, as well as retinal endothelial P-selectin expression. Our data suggest an important role for VAP-1 in the recruitment of leukocytes to the immune-privileged ocular tissues during acute inflammation. VAP-1 inhibition may become a novel strategy in the treatment of ocular inflammatory diseases.
authors.affiliation: Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Miyahara
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Lama
authors.initials: L
authors.lastname: Almulki
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.forename: Toshio
authors.initials: T
authors.lastname: Hisatomi
authors.forename: Haicheng
authors.initials: H
authors.lastname: She
authors.forename: Kennard L
authors.initials: KL
authors.lastname: Thomas
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Garland
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Evangelos S
authors.initials: ES
authors.lastname: Gragoudas
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawai
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Mashima
authors.forename: Ali
authors.initials: A
authors.lastname: Hafezi-Moghadam
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000818:Animals; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D002522:Chlorocebus aethiops; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D012160:Retina / Q000378:metabolism; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D015815:Cell Adhesion Molecules; D004731:Endotoxins; D004791:Enzyme Inhibitors; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat