Key Molecules involved in the Early Phase of Anterior Uveitis

参与前葡萄膜炎早期阶段的关键分子

• 批准号: 09671793
• 负责人: MANDAI Michiko
• 金额: $ 2.18万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671793/
• 关键词: LPS; cellular infiltration; endotoxin-induced uveitis; E-selectin; P-selectin; estrpgen; gene expression; vaxcular endothelium; エンドトキシンぶどう膜炎; タモキシフェン; モノクローナル抗体

Endotoxin-induced uveitis (EIU) is an animal model of acute ocular inflammation caused by the injection of lipopolysaccharide (LPS). Selectins area group of molecules involved in rolling of leukocytes, the initial step of cellular infiltration. Among them, P-selectin is stored in the vascular endothelial cell body and translocated to the surface upon stimulation, whereas E-selectin is regulated at the transcriptional level of the gene. In EIU, we found that P-selectin appeared immunohistochemically on the endothelial surface of the vessels of iris-ciliary body after 15 minutes of LPS treatment, followed by its second expression at 3-5 hours after LPS injection, and that E-selectin appeared 7-24 hours after LPS treatment. Each of the neutralizing antibodies against P- and E-selectin similarly reduced the cellular infiltration in EIU, but anti P-selectin antibody given at 6 hours after LPS treatment did not significantly inhibit the cellular infiltration whereas anti E-selectin antibody … More given at any time after LPS treatment significantly reduced cellular infiltration thereafter. Semi-quantitative PCR revealed that E-selectin gene expression reached a peak at 6 hours after LPS treatment both in the iris-ciliary body and retina, and it returned to the basal level at the time of maximum uveitis. Simultaneous injection of anti P-and E-selectin antibodies almost abrogated cellular infiltration. These suggested that P-selectin is involved in the initiation of cellular infiltration whereas E-selectin contributes to retain cellular infiltration ; the inhibition of the former may contribute to the prevention of inflammation and the latter, to the early resolution of the inflammation. Next we focused on the fact that anterior uveitis associated with massive cellular infiltration is more often observed in men than in women, and we are studying the role of estrogen against cellular infiltration in EIU.Estrogen receptor-like immunoreactivity was found on the vascular endothelium of iris-ciliary body, and the degree of cellular infiltration was in the order of male>ovariectomized female>female rats. Intraperitoneal injection of estradiol significantly reduced cellular infiltration and the E-selectin gene expression, indicating that estrogen protects against cellular infiltration by modulation the selectin expression. Less

内毒素诱导的葡萄膜炎（EIU）是由注射脂多糖（LPS）引起的急性眼部炎症的动物模型。选择素是一组参与白细胞滚动的分子，是细胞浸润的初始步骤。其中，P-选择素储存在血管内皮细胞体中，并在刺激时易位到表面，而E-选择素在基因的转录水平上受到调节。在EIU中，我们发现LPS处理15分钟后，虹膜睫状体血管内皮细胞表面出现P-选择素，LPS处理后3-5小时出现第二次表达，LPS处理后7-24小时出现E-选择素。抗P-和E-选择素的中和抗体均能类似地减少EIU中的细胞浸润，但在LPS处理后6小时给予抗P-选择素抗体并不能显著抑制细胞浸润，而抗E-选择素抗体则不能显著抑制细胞浸润。 ...更多信息 在LPS处理后的任何时间给药显著降低此后的细胞浸润。半定量PCR结果显示，E-选择素基因在LPS处理后6 h在虹膜睫状体和视网膜中的表达均达到高峰，并在最大葡萄膜炎时恢复到基础水平。同时注射抗P-和E-选择素抗体几乎废除细胞浸润。这些表明，P-选择素参与细胞浸润的启动，而E-选择素有助于保持细胞浸润;抑制前者可能有助于预防炎症，后者可能有助于炎症的早期消退。在EIU中，我们观察到虹膜睫状体血管内皮细胞有雌激素受体样免疫反应，细胞浸润程度为雄性>去卵巢雌性>雌性。腹腔注射雌二醇可显著降低细胞浸润和E-选择素基因表达，表明雌激素通过调节选择素表达来保护细胞免受浸润。少