Blocking both E-Selectin and P-Selectin Inhibits Endotoxin-Induced Leukocyte Infiltration into the Eye

doi:10.1006/clin.1996.4324

Clinical Immunology and Immunopathology

Volume 83, Issue 1, April 1997, Pages 45-52

Clinical Immunology ...

https://doi.org/10.1006/clin.1996.4324 Get rights and content

Abstract

The initial contact between leukocytes and the vascular endothelium at sites of inflammation is mediated by selectins. The purpose of this study was to investigate the role of the two selectins expressed on the vascular endothelium, E-selectin and P-selectin, in the pathogenesis of endotoxin-induced uveitis. Endotoxin-induced uveitis was produced in female C3H/HeN mice usingSalmonella typhimuriumendotoxin injected into one hind footpad. At the time of endotoxin injection mice were treated with an intraperitoneal injection of a monoclonal antibody against E-selectin or P-selectin, a combination of both anti-selectin antibodies, or isotype-matched control antibodies. In a second set of experiments, antibody treatment was administered 6 hr after endotoxin injection, when inflammatory cells are already entering the eye. Ocular inflammation was graded histologically by a masked observer. When administered at the time of endotoxin injection, anti-P-selectin antibody decreased ocular inflammation by 37% compared to control animals (P= 0.05). There was no statistical decrease in ocular inflammation in animals treated with anti-E-selectin antibody. The combination of anti-P-selectin and anti-E-selectin antibodies decreased infiltrating inflammatory cells by 61% (P< 0.01). When treatment was delayed until 6 hr after endotoxin injection, the combination of anti-P-selectin and anti-E-selectin antibodies again decreased ocular inflammation by 60% (P< 0.01). Immunohistochemical staining showed decreased ICAM-1 expression in the eyes of animals treated with the combination of anti-P- and anti-E-selectin antibodies. Blocking both P-selectin and E-selectin resulted in a significant decrease in endotoxin-induced intraocular inflammation.

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Cited by (29)

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2005, Microvascular Research
The microvasculature of the eye plays a critical role in many ophthalmic diseases, including diabetic retinopathy and macular degeneration. Transcriptional profiling by gene array allows characterization of endothelial cells (EC) and can test for inherent EC diversity relative to the tissue source of the EC. Here, we established highly purified microvascular EC cultures from donor-matched human irises and retinae (4 donor pairs). We used nylon-based gene array kits to compare gene expression in paired confluent EC monolayers, under both quiescent and inflammatory agent (bacterial lipopolysaccharide, LPS; or tumor necrosis-factor alpha, TNFα)-activated conditions. In the absence of an inflammatory agent, iris and retinal ECs from the same donor were remarkably similar in overall gene expression profiles, except for possible differences in the expression of platelet-derived growth factor-A and a DNA mismatch repair protein (mutL homologue). Several detectable transcripts had never previously been reported in the eye. After inflammatory stimulation, significantly greater expression of the adhesion molecule E-selectin mRNA was consistently detected in retinal versus iris EC, and this difference was maintained at the protein level both in cell-surface-expressed and secreted soluble E-selectin protein in paired cultures. Thus, cultured EC derived from adjacent microvascular beds are biologically distinct. Such endothelial diversity could play a role in the pathogenesis of tissue-specific inflammation, infection, neovascularization, and malignancy.
Suppressive effects of histamine H1 receptor antagonist diphenhydramine on the leukocyte infiltration during endotoxin-induced uveitis
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Histamine has been shown to play an important role in the step of leukocyte rolling, the initial step to leukocyte infiltration into an inflamed region. We investigated the roles of histamine in the leukocyte recruitment during endotoxin-induced uveitis (EIU) in vivo using acridine orange digital fluorography. An injection of histamine into the vitreous cavity of a Lewis rat induced leukocyte rolling along the major retinal veins. In other experiments, EIU was induced in Lewis rats by footpad injection of lipopolysaccharide (LPS). Leukocyte rolling was also observed in the retinal veins of EIU rats. To block the histamine H1 receptor, diphenhydramine (DPH) was administered intraperitoneally 15 min before the LPS injection. DPH significantly inhibited leukocyte rolling along the major retinal veins of EIU rats, suppressing leukocyte infiltration into the vitreous cavity. The vasodilation in EIU was also significantly suppressed with DPH. Moreover, leukocyte infiltration into aqueous humor was significantly suppressed in DPH-treated rats. Although the inhibitory effects of DPH was less obvious at later time points, addition of DPH every 12 hr showed prolonged anti-inflammatory effects up to 48 hr after LPS injection. In contrast, protein leakage into the aqueous humor was not suppressed as much as leukocyte infiltration with DPH. These results suggest that histamine would play a pivotal role in leukocyte recruitment during EIU in rats. Blocking the histamine H1 receptor might help to prevent or minimize leukocyte infiltration in uveitis.
In vivo neutralization of P-selectin inhibits leukocyte-endothelial interactions in retinal microcirculation during ocular inflammation
1998, Microvascular Research
P-selectin is one of the adhesion molecules involved in leukocyte rolling during an inflammatory reaction. The aim of this study was to examine the role of P-selectin in leukocyte–endothelial interactions in retinal microcirculation during ocular inflammation, known as endotoxin-induced uveitis (EIU),in vivo.EIU was induced in Lewis rats by footpad injection of lipopolysaccharide (LPS). At the time of LPS treatment or 12 h later, anti-rat P-selectin mAb (ARP) was injected intravenously, and its effect on leukocyte behavior in the retina was studied after intravital staining with acridine orange using a scanning laser ophthalmoscope. P-selectin gene expression in the retina was also studied by a semiquantitative polymerase chain reaction (PCR) method. Administration of ARP at the time of LPS treatment significantly reduced the number of rolling leukocytes at 6 and 12 h by 68% (P< 0.05) and 83% (P< 0.01), respectively, and the number of cells infiltrating the vitreous at 48 h by 61% (P< 0.05). Interestingly, ARP significantly inhibited the vasodilation observed during EIU. In contrast, delayed administration of ARP blocked neither cellular infiltration nor vasodilation. P-selectin gene expression was upregulated during the course of EIU. In conclusion, P-selectin may significantly contribute to the development of inflammation in the early stage of endotoxin-induced ocular inflammation.
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Regular ArticleBlocking both E-Selectin and P-Selectin Inhibits Endotoxin-Induced Leukocyte Infiltration into the Eye

Abstract

Cell

Cell

Cell

Exp. Eye Res.

Immunity

Biochem. Biophys. Res. Commun.

Exp. Eye Res.

Cell

Cell

Neutrophils roll on E-selectin

J. Immunol.

Two-step model of leukocyte-endothelial cell interaction in inflammation: Distinct roles for LECAM-1 and the leukocyte β2 integrins in vivo

Proc. Natl. Acad. Sci. USA

Differences between human eosinophils and neutrophils in the function and expression of sialic acid-containing counterlignads for E-selectin

J. Immunol.

Identification of an inducible endothelial-leukocyte adhesion molecule

Proc. Natl. Acad. Sci. USA

Endothelial leukocyte adhesion molecule-1: An inducible receptor for neutrophils related to complement regulatory proteins and lectins

Science

GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies

J. Clin. Invest.

Regular Article
Blocking both E-Selectin and P-Selectin Inhibits Endotoxin-Induced Leukocyte Infiltration into the Eye