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K. Noda, S. Miyahara, T. Nakazawa, T. Hisatomi, L. Almulki, H. She, S. Nakao, J. W. Miller, E. S. Gragoudas, A. Hafezi-Moghadam; Blockade of Vascular Adhesion Protein-1 Suppresses Endotoxin Induced Uveitis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5124.
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© ARVO (1962-2015); The Authors (2016-present)
Vascular adhesion protein-1 (VAP-1), a 170-kDa homodimeric sialylated glycoprotein, mediates transendothelial migration of lymphocytes and granulocytes to normal and inflamed tissues. Our recent data show that in ocular tissues, VAP-1 is located on vascular endothelial cells in the choroid and retina. However, whether VAP-1 contributes to leukocyte recruitment during ocular inflammation is not known. Here, we investigate the therapeutic effect of a novel VAP-1 inhibitor on ocular inflammation in Endotoxin Induced Uveitis (EIU).
EIU was induced in male Lewis rats by injection of 100µg LPS into one hind footpad. Immediately after LPS injection, the VAP-1 inhibitor, U-V002, was administered systemically (0.3mg/kg), while control animals were injected with vehicle. The number of infiltrating cells and the protein concentration in the aqueous humor were quantified in normal and EIU animals with or without inhibitor treatment. To quantify the number of extravasated leukocytes into the inflamed retina, acridine orange (AO) staining of infiltrated leukocytes was conducted. Furthermore, leukocyte accumulation in retinas of inflamed EIU animals was evaluated in histological sections by CD45 staining.
At 24 hrs after LPS injection, VAP-1 inhibition significantly reduced the cell infiltration and the protein concentration in the aqueous humor of EIU animals by 41% (p<0.05) and 53% (p<0.01), respectively. Furthermore, VAP-1 inhibition led to suppression of leukocyte transmigration in the EIU retina. AO staining revealed that retinal leukocyte extravasation in VAP-1 treated rats was significantly reduced by 30.1%, 60.4%, 54.6%, and 40.9% at 4, 10, 24, and 48 hours after LPS injection, respectively (p<0.05). CD45 staining showed that leukocyte accumulation in the EIU retina was significantly lower in the inhibitor-treated rats compared to the vehicle-treated animals at 24 hrs after LPS stimulation (3±1.26 cells vs. 51.2±15.35 cells, p<0.01).
The current data suggest an important role for VAP-1 in the recruitment of leukocytes to ocular tissues during inflammation. VAP-1 inhibition may thus be a novel and potent therapeutic approach for the treatment of ocular inflammation.
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