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

ABSTRACT: 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.

SUBMITTER: Yamashiro K

PROVIDER: S-EPMC1771581 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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

Yamashiro K K 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

The British journal of ophthalmology 20030401 4

<h4>Background</h4>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.<h4>Methods</h4>EIU was induced in Lewis rats b ...[more]

PMID: 12642314

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Project description:Background and purposeCannabinoid CB2 receptors mediate immunomodulation. Here, we investigated the effects of CB2 receptor ligands on leukocyte-endothelial adhesion and inflammatory mediator release in experimental endotoxin-induced uveitis (EIU).Experimental approachEIU was induced by intraocular injection of lipopolysaccharide (LPS, 20?ng·?L(-1) ). Effects of the CB2 receptor agonist, HU308 (1.5% topical), the CB2 receptor antagonist, AM630 (2.5?mg·kg(-1) i.v.), or a combination of both compounds on leukocyte-endothelial interactions were measured hourly for 6?h in rat iridial vasculature using intravital microscopy. Anti-inflammatory actions of HU308 were compared with those of clinical treatments for uveitis - dexamethasone, prednisolone and nepafenac. Transcription factors (NF-?B, AP-1) and inflammatory mediators (cytokines, chemokines and adhesion molecules) were measured in iris and ciliary body tissue.Key resultsLeukocyte-endothelium adherence was increased in iridial microvasculature between 4-6?h after LPS. HU308 reduced this effect after LPS injection and decreased pro-inflammatory mediators: TNF-?, IL-1?, IL-6, CCL5 and CXCL2. AM630 blocked the actions of HU-308, and increased leukocyte-endothelium adhesion. HU-308 decreased levels of the transcription factors NF-?B and AP-1, while AM630 increased levels of NF-?B. Topical treatments with dexamethasone, prednisolone or nepafenac, failed to alter leukocyte adhesion or mitigate LPS-induced increases in inflammatory mediators during the 6?h of EIU.Conclusion and implicationsActivation of CB2 receptors was anti-inflammatory in a model of acute EIU and involved a reduction in NF-?B, AP-1 and inflammatory mediators. CB2 receptors may be promising drug targets for the development of novel ocular anti-inflammatory agents.Linked articlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6.

Project description:PurposeUveitis is a common cause of vision loss. The renin angiotensin system (RAS), which plays a vital role in cardiovascular system, is a potent mediator of inflammation and has been implicated in the pathogenesis of uveitis. A newly identified axis of RAS, ACE2/Ang-(1-7)/Mas, has emerged as a novel target because it counteracts the deleterious effect of angiotensin II. The purpose of this study was to investigate the effect of endogenous ACE2 activation in preventing endotoxin-induced uveitis (EIU) in mice.MethodsACE2 activator diminazene aceturate (DIZE) was administered both systemically and locally. For systemic administration, female BALB/c mice received intraperitoneal injection of DIZE (60 mg/kg body weight [BW]) for 2 days prior to lipopolysaccharide (LPS) intravitreal injection (125 ng) to induce uveitis. For local study, DIZE was given at 0.5, 0.1, and 0 mg/mL as eyedrops six times per day for 2 days before LPS injection. The anterior segment of the mice was examined at 12, 24, 48, and 72 hours after LPS injection, and clinical scores were determined at the same time. Morphology and infiltrating inflammatory cells were evaluated after 24 hours. The mRNA levels of inflammatory cytokines were analyzed by real-time RT-PCR. ACE2 activity was determined using a self-quenching fluorescent substrate.ResultsAt 24 hours, the clinical score of mice treated with DIZE systemically was significantly lower (mean, ∼1.75) than the saline vehicle group (mean, ∼4) (P < 0.001). Histological examination showed 63.4% reduction of infiltrating inflammatory cells in the anterior segment and 57.4% reduction in the posterior segment of DIZE-treated eyes. The number of CD45(+) inflammatory cells in the vitreous of the DIZE-treated group was decreased (43.3%) compared to the vehicle group (P < 0.01). The mRNA levels of inflammatory cytokines were significantly reduced in the DIZE-treated group (P < 0.01, P < 0.001). The number of infiltrating inflammatory cells was also significantly reduced in eyes that received topical administration of DIZE: 73.8% reduction in the 0.5 mg/mL group and 51.7% reduction in the 0.1mg/mL group compared to the control group. DIZE treatment resulted in significantly increased ACE2 activity in the retina (P < 0.001).ConclusionsEndogenous ACE2 activation by DIZE has a preventive effect on LPS-induced ocular inflammation in the EIU mouse model. These results support the notions that RAS plays a role in modulating ocular immune response and that enhancing ACE2 provides a novel therapeutic strategy for uveitis.

Dataset Information

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

Publications

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

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