Therapeutic trial of sialyl Lewis^x analogue on airway inflammation in asthma

唾液酸化Lewis^x类似物对哮喘气道炎症的治疗试验

• 批准号: 12670569
• 负责人: INOUE Hiroshi
• 金额: $ 2.62万
• 依托单位: Iwate Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670569/
• 关键词: adhesion molecule; p-selectin; E-selectin; inflammation; lymphocyte; sialyl Lewis^x; mice; 喘息; 好酸球; セレクチン; sialy Lewisx; 気管支喘息; 気道炎症; E-eレクチン; シアリルルイスX; 好酸球浸潤; 動物モデル

At the site of inflammation, adhesion molecules such as ICAM-1, VCAM-1, E- and P-selectins are expressed on the surface of endothelial cells, on the other hand, Mac-1, VLA-4 and sialyl Lewis^x are expressed on the surface of inflammatory cells. These molecules interact each other and play an important roles in traffic of cells from blood vessels to tissue. In this regard, sialyl Lewis^x analogue is hypothesized to suppress the inflammatory responses by inhibiting the binding between selectins and sialyl Lewis^x. To examine this hypothesis, we evaluated the effect of SLX analogue on pathological changes in the experimental mouse model.After sensitization, we determined the responses of mice with transnasally administered Micropolyspora faeni (Mf), then SLX analogue was delivered by intraperitoneally or administered transnasally. Mice exposed to antigen (positive control) showed the increases of the number of lymphocyte ratio in their bronchoalveolar lavage fluids to compare the controls. In mice treated with sialyl Lewis^x, they were significantly lower than those in positive control. In addition, histological scores of mice treated with sialyl Lewis^x, which were determined according to previous reports, were significantly lower than that of positive control. In addition, expression of E- and P- selectins in endothelial cells of pulmonary arterioles were evaluated with immunohistochemistry, These results suggested that the interaction between selectins, such as E-selectin, and sialyl Lewis^x play a critical role in inflammatory cell infiltration in the lung of mice, and sialyl Lewis^x analogue may be a possible therapeutic drug to suppress pulmonary inflammatory response.

在炎症部位，粘附分子如ICAM-1、VCAM-1、E-和P-选择素在内皮细胞的表面上表达，另一方面，Mac-1、VLA-4和唾液酸刘易斯-α x在炎性细胞的表面上表达。这些分子相互作用，并在细胞从血管到组织的运输中发挥重要作用。在这方面，假设sialyl刘易斯^x类似物通过抑制选择素和sialyl刘易斯^x之间的结合来抑制炎症反应。为了验证这一假设，我们在实验小鼠模型上评价了SLX类似物对病理变化的影响，致敏后，通过鼻内给药法氏小多孢菌（Micropolysporafaeni，Mf）来测定小鼠的反应，然后通过腹腔内或鼻内给药SLX类似物。暴露于抗原（阳性对照）的小鼠显示其支气管肺泡灌洗液中淋巴细胞比率的数量增加，以与对照相比。在用sialyl刘易斯^x处理的小鼠中，它们显著低于阳性对照中的那些。此外，根据先前的报道测定的用唾液酸化刘易斯^x处理的小鼠的组织学评分显著低于阳性对照。结果提示，选择素（如E-选择素）与唾液酸刘易斯-x的相互作用在小鼠肺内炎症细胞浸润中起重要作用，唾液酸刘易斯-x类似物可能成为抑制肺部炎症反应的治疗药物。

项目成果

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