Inhibitory effects of antithrombin III against leukocyte rolling and infiltration during endotoxin-induced uveitis in rats.
OBJECTIVE
This study was designed to investigate the suppressive effects of antithrombin (AT)III on inflammatory reactions during endotoxin-induced uveitis (EIU) in rats by studying leukocyte-endothelium interactions.


METHODS
EIU was induced in Lewis rats by footpad injection of lipopolysaccharide (LPS). ATIII was administered immediately after or at 6 hours after LPS injection. Its suppressive effects on inflammatory leukocyte behavior were evaluated in vivo with acridine orange digital fluorography. Clinical signs of inflammation were also examined, and aqueous humor (AH) was collected to evaluate leukocyte infiltration and protein leakage. In a separate experiment, P-selectin mRNA expression was studied in the iris-ciliary body (ICB) and the retina.


RESULTS
After treatment with ATIII, leukocyte rolling was substantially inhibited along the retinal veins, suppressing subsequent leukocyte infiltration into the vitreous cavity. Similarly, leukocyte infiltration and protein leakage into the AH were significantly reduced with ATIII treatment. The clinical grade of EIU was substantially lower in ATIII-treated rats. In addition, delayed administration of ATIII after EIU induction significantly attenuated these inflammatory reactions. The levels of P-selectin mRNA expression in both ICB and retina, which were upregulated after LPS injection, were substantially lower in the ATIII-treated rats.


CONCLUSIONS
ATIII treatment significantly inhibited inflammatory reactions induced with LPS. Its suppressive effects on P-selectin expression could contribute to the attenuation of leukocyte infiltration, possibly by inhibiting leukocyte rolling. The current findings suggest that ATIII may have a role in the management of patients with uveitis.
Yamashiro
K
K
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Japan. Department of Ophthalmology, Nagoya City University Medical School, Japan.
Kiryu
J
J
Tsujikawa
A
A
Honjo
M
M
Nonaka
A
A
Miyamoto
K
K
Honda
Y
Y
Tanihara
H
H
Ogura
Y
Y
D000818:Animals; D000990:Antithrombin III / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D002924:Ciliary Body / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D007498:Iris / Q000378:metabolism; D007958:Leukocyte Count; D007962:Leukocytes / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D019007:P-Selectin / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000378:metabolism; D012486:Salmonella typhimurium; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014822:Vitreous Body / Q000473:pathology
D008070:Lipopolysaccharides; D019007:P-Selectin; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III