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Suppressive effects of selectin inhibitor SKK-60060 on the leucocyte infiltration during endotoxin induced uveitis

¹ Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
² Drug Discovery Research Department, Sanwa Kagaku Kenkyusho Co Ltd, Mie, Japan
³ Department of Ophthalmology, Nagoya City University Medical School, Nagoya, Japan

Correspondence to:
Correspondence to:
Dr Junichi Kiryu, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Japan;
kiryu{at}kuhp.kyoto-u.ac.jp

Background: It is well known that selectin is involved in the development of endotoxin induced uveitis (EIU), and has a major role in leucocyte infiltration. Recently, a novel selectin inhibitor (SKK-60060) that can block P and L selectins in vitro has been developed. This study was designed to investigate the anti-inflammatory effects of SKK-60060 on the inflammatory reaction during EIU in rats by studying leucocyte-endothelium interactions.

Methods: EIU was induced in Lewis rats by footpad injection of lipopolysaccharide (LPS). SKK-60060 was administered 15 minutes before LPS injection, and its suppressive effects on inflammatory leucocyte behaviour were evaluated in vivo with acridine orange digital fluorography; the diameters of retinal arteries and veins were also measured. After these studies, aqueous humour was collected to evaluate leucocyte infiltration and protein leakage.

Results: After LPS injection, rolling leucocytes were observed in major retinal veins, followed by leucocyte infiltration into the vitreous cavity. Following treatment with SKK-60060, leucocyte rolling was significantly inhibited in the retinal veins (p <0.01), and subsequent leucocyte infiltration into the vitreous cavity was also significantly suppressed (p <0.01). Retinal vasodilation was also substantially suppressed in SKK-60060 treated rats (p <0.01). Similarly, leucocyte infiltration and protein leakage into the aqueous humour were reduced significantly by SKK-60060 (p <0.01).

Conclusions: SKK-60060 treatment significantly inhibited the inflammatory reaction induced by LPS. Its inhibitory effects on P and L-selectin resulted in suppression of leucocyte infiltration and the subsequent inflammatory reaction caused by accumulated leucocytes. The current findings suggest that SKK-60060 may be useful in the management of uveitis.

Keywords: anti-inflammatory agents; leucocytes; selectins; uveitis

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