In VivoNeutralization of P-Selectin Inhibits Leukocyte–Endothelial Interactions in Retinal Microcirculation during Ocular Inflammation

Miyamoto, Kazuaki; Ogura, Yuichiro; Hamada, Muneo; Nishiwaki, Hirokazu; Hiroshiba, Naoko; Tsujikawa, Akitaka; Mandai, Michiko; Suzuma, Kiyoshi; Tojo, Shinichiro J.; Honda, Yoshio

doi:10.1006/mvre.1998.2084

Cited by 24 publications

(33 citation statements)

References 25 publications

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“…This radical-scavenging activity could be one of the mechanism of the inhibition of leukostasis observed in this study, because leukocytes in diabetic animals have been reported to be more activated [1,4] and produce more oxygen-derived free radicals [5,6], which induce vascular endothelial dysfunction [7,8,9]. Recent studies demonstrated the increased expression of adhesion molecules under diabetic conditions [2,7,10,26,35]. The interference by gliclazide with the increase in adhesion molecule expression could be another possibility, although it has not been examined in this study.…”

Section: Discussionmentioning

confidence: 76%

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Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Kinoshita¹,

Kakehashi²,

Inoda

et al. 2002

Diabetologia

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Aims/hypothesis. Early stage leukocyte entrapment in the retinal microcirculation (retinal leukostasis) is considered to be one of the important pathogenetic events in diabetic retinopathy. Gliclazide, a sulphonylurea, was reported to reduce leukocyte adhesion to endothelial cells in hyperglycaemia in vitro, thus suggesting possible selective efficacy of this sulphonylurea in preventing leukostasis in diabetic patients. This study evaluated the effectiveness and selectivity of gliclazide treatment on retinal leukostasis of diabetic rats in vivo. Methods. Streptozotocin (STZ) (65 mg/kg)-induced diabetic rats were divided into three groups (n = 8 each): an untreated diabetic group, a gliclazide-treated diabetic group, and a glibenclamide-treated diabetic group. Gliclazide or glibenclamide was administered orally during a 3-week period. Non-diabetic rats were used as a control (n = 8). Retinal leukostasis was quantitatively evaluated in vivo by acridine orange leukocyte fluorography using a scanning laser ophthalmoscope.Results. The number of leukocytes trapped in the area around the optic disc in the untreated diabetic group (36.9 ± 5.1 cells) increased significantly compared with the non-diabetic control group (21.9 ± 2.9 cells; p = 0.0007). The number of leukocytes trapped in the gliclazide-treated diabetic group (23.5 ± 4.0 cells) decreased significantly compared with untreated diabetic group (p = 0.0008). In contrast, no reduction of retinal leukostasis was found in the glibenclamide-treated diabetic group (37.8 ± 5.8 cells; p = 0.7923). Conclusion/interpretation. This suggests that gliclazide could directly improve abnormalities in the retinal microcirculation independent of blood glucose control and possibly have selective therapeutic benefits in preventing early, critical events in diabetic retinopathy compared with other sulphonylurea drugs. [Diabetologia (2002) 45:735-739] Keywords Gliclazide, sulphonylurea, diabetic retinopathy, retinal leukostasis, acridine orange leukocyte fluorography, scanning laser ophthalmoscope. Diabetic retinopathy is a leading cause of adult vision loss and blindness and early-stage, preventive strategies are important research areas. Leukocyte adhesion to the diabetic retinal vasculature is presumed to be the critical early event in the pathogenesis of diabetic retinopathy [1,2,3], resulting in a breakdown in the blood-retinal barrier and in capillary nonperfusion [1,4,5,6,7,8,9,10,11,12]. In a rat model of diabetic retinopathy, investigators demonstrated retinal capillary occlusion by neutrophils and monocytes in histologic sections and found that areas of endothelial cell damage, capillary loss, and leukocyte extravasation existed adjacent to the static leukocytes [1]. In another post mortem study of human subjects, increased numbers of neutrophils were observed in the choroid and retina of patients with diabetes [2].

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Section: Discussionmentioning

confidence: 76%

“…AOLF used in this study was a simple, newly-established technique that is useful for the study of microcirculation in the retina [3,7,10,19,20,23,24,25,26,27,28]. Under the SLO, we observed directly the behaviour of circulating leukocytes in the retina.…”

Section: Discussionmentioning

confidence: 99%

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Kinoshita¹,

Kakehashi²,

Inoda

et al. 2002

Diabetologia

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“…Leukocyte-endothelial interactions in the LPS-simulated retina occurred in a later phase than expected in other organs. 26,27 There might be regional differences in leukocyte recruitment timing during endotoxic sepsis. It would appear from the present and previous studies that P-selectin plays a central role in leukocyte rolling in the LPS-stimulated retina.…”

Section: Discussionmentioning

confidence: 99%

“…The number of leukocytes that infiltrated the vitreous cavity was defined as the number of leukocytes in the vitreous cavity within a circle with a 1-disk-diameter radius from the center of the optic disc 20 minutes after AO injection. 26,27 Rolling platelets were defined as platelets that moved at a slower velocity than free-flowing platelets in a given vessel. The number of rolling platelets was calculated from the number crossing a fixed area of the vessel at a distance 1 disc diameter from the optic disc center per minute.…”

Section: Image Analysismentioning

confidence: 99%

Interactions Between Blood Cells and Retinal Endothelium in Endotoxic Sepsis

et al. 2000

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Abstract-Platelets and leukocytes are thought to play a leading role in the pathogenesis of many inflammatory conditions.To recruit flowing blood cells to the inflammatory region, it would be necessary for them to interact with vascular endothelial cells. Recently, many reports have indicated the resistance of spontaneous hypertensive rats (SHR) to endotoxic sepsis. Their resistance might be derived from suppressed interaction between these blood cells and endothelial cells. Therefore, SHR and age-matched Wistar-Kyoto rats (WKY) were induced with endotoxic sepsis by intravenous injection of lipopolysaccharide (LPS). At 4, 12, 24, and 48 hours after induction, leukocyte-endothelial interactions in the retina were evaluated in vivo with acridine orange digital fluorography. Fluorescently labeled platelets were also injected to investigate platelet-endothelial interactions in the retina in endotoxic sepsis. Leukocyte rolling in SHR after LPS injection was significantly suppressed; the maximum number of rolling leukocytes was reduced by 80.1% at 12 hours after LPS injection in SHR compared with WKY. Subsequent leukocyte infiltration into the vitreous cavity was significantly inhibited in SHR. Furthermore, platelet-endothelial interactions in the retina were also suppressed in SHR treated with LPS. The maximum numbers of rolling and adherent platelets were reduced by 59.5% and 62.6%, respectively, in SHR compared with WKY. In both strains, leukocyte-and platelet-endothelial interactions were substantially inhibited by the blocking of P-selectin. These suppressed interactions could contribute to the reduction of leukocyte-and platelet-mediated tissue injury in endotoxic sepsis in SHR, resulting in their resistance to endotoxemia. (Hypertension. 2000;36:250-258.)

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“…The breakdown of blood ocular barriers can lead to upregulation of adhesion molecules, leukocyte infiltration (19,27,30,38,40,67), and release of inflammatory mediators, which intensify and maintain inflammation (32,37,60). BRB permeability occurs during inflammation in an experimental autoimmune uveoretinitis model where leukocytes play an active role in permeability and tight junction disruption (68).…”

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confidence: 99%

Bacillus cereusInduces Permeability of an In Vitro Blood-Retina Barrier

Moyer¹,

Ramadan

Thurman³

et al. 2008

Infect Immun

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Most Bacillus cereus toxin production is controlled by the quorum-sensing-dependent, pleiotropic global regulator plcR, which contributes to the organism's virulence in the eye. The purpose of this study was to analyze the effects of B. cereus infection and plcR-regulated toxins on the barrier function of retinal pigment epithelium (RPE) cells, the primary cells of the blood-retina barrier. Human ARPE-19 cells were apically inoculated with wild-type or quorum-sensing-deficient B. cereus, and cytotoxicity was analyzed. plcR-regulated toxins were not required for B. cereus-induced RPE cytotoxicity, but these toxins did increase the rate of cell death, primarily by necrosis. B. cereus infection of polarized RPE cell monolayers resulted in increased barrier permeability, independent of plcR-regulated toxins. Loss of both occludin and ZO-1 expression occurred by 8 h postinfection, but alterations in tight junctions appeared to precede cytotoxicity. Of the several proinflammatory cytokines analyzed, only interleukin-6 was produced in response to B. cereus infection. These results demonstrate the deleterious effects of B. cereus infection on RPE barrier function and suggest that plcRregulated toxins may not contribute significantly to RPE barrier permeability during infection.

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In VivoNeutralization of P-Selectin Inhibits Leukocyte–Endothelial Interactions in Retinal Microcirculation during Ocular Inflammation

Cited by 24 publications

References 25 publications

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Interactions Between Blood Cells and Retinal Endothelium in Endotoxic Sepsis

Bacillus cereusInduces Permeability of an In Vitro Blood-Retina Barrier

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