Suppressive effects of selectin inhibitor SKK-60060 on the leucocyte infiltration during endotoxin induced uveitis.
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.
Yamashiro
K
K
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kiryu
J
J
Tsujikawa
A
A
Nonaka
A
A
Nishijima
K
K
Kamizuru
H
H
Miyamoto
K
K
Honda
Y
Y
Jomori
T
T
Ogura
Y
Y
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004187:Disaccharides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology; D005471:Fluoroscopy / Q000379:methods; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides; D051381:Rats; D011917:Rats, Inbred Lew; D019087:Selectins / Q000502:physiology*; D014605:Uveitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D000893:Anti-Inflammatory Agents; D004187:Disaccharides; D008070:Lipopolysaccharides; C414367:SKK 60060; D019087:Selectins