Kilgore K S, Powers K L, Imlay M M, Malani A, Allen D I, Beyer J T, Anderson M B, Warren J S
Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
J Pharmacol Exp Ther. 1998 Jul;286(1):439-46.
We examined the protective effects of GM2941, a sulfated glycomimetic of the complex carbohydrate sialyl Lewis(x), in a model of pulmonary granuloma development. This study was based on the rationale that formation of glucan-induced lung granulomas is dependent on neutrophils and that sialyl Lewis(x) glycomimetic (GM2941) interferes, in vitro, with P-selectin-dependent neutrophil-endothelial adhesive interactions. Infusion of particulate yeast cell wall glucan into rats results in the rapid (48 hr) formation of monocyte/macrophage-rich angiocentric pulmonary granulomas. Development of granulomas exhibits a temporal pattern characterized by the early, transient influx of neutrophils into blood vessel walls at sites of glucan embolization, followed by accumulation of monocytes and macrophages that constitute the definitive angiocentric lesions. Within 1 hr after the infusion of glucan, immunohistochemical analysis revealed up-regulation of blood vessel wall-associated P-selectin. Previous studies utilizing neutrophil-depleted animals have revealed that neutrophils, although not present in definitive lesions, are required for full granuloma development. The potential of GM2941 to inhibit neutrophil-endothelial cell adhesive interactions was demonstrated by the ability of the compound to inhibit P-selectin-mediated adhesion to histamine-stimulated HUVECs. Infusion of GM2941 retarded pulmonary granuloma development in a dose-dependent manner. Whole-lung myeloperoxidase activity, measured at the time of peak neutrophil accumulation, was significantly reduced in animals pretreated with GM2941 (30 mg/kg, 24 microM/kg), which suggests that this compound affords protection, at least in part, through impedance of neutrophil recruitment. These data indicate that GM2941 affords a significant degree of protection against granuloma formation associated with glucan infusion, probably through the interruption of neutrophil recruitment.
我们在肺部肉芽肿形成模型中研究了GM2941（一种复合碳水化合物唾液酸化路易斯x的硫酸化糖模拟物）的保护作用。本研究基于以下理论依据：葡聚糖诱导的肺肉芽肿形成依赖于中性粒细胞，且唾液酸化路易斯x糖模拟物（GM2941）在体外可干扰P-选择素依赖性中性粒细胞与内皮细胞的黏附相互作用。向大鼠输注颗粒状酵母细胞壁葡聚糖会导致富含单核细胞/巨噬细胞的血管中心性肺肉芽肿迅速形成（48小时）。肉芽肿的形成呈现出一种时间模式，其特征为在葡聚糖栓塞部位，中性粒细胞早期短暂流入血管壁，随后单核细胞和巨噬细胞聚集，构成最终的血管中心性病变。在输注葡聚糖后1小时内，免疫组织化学分析显示血管壁相关的P-选择素上调。先前利用中性粒细胞耗竭动物进行的研究表明，中性粒细胞虽然不存在于最终病变中，但对于肉芽肿的完全形成是必需的。GM2941抑制中性粒细胞与内皮细胞黏附相互作用的潜力通过该化合物抑制P-选择素介导的与组胺刺激的人脐静脉内皮细胞（HUVECs）黏附的能力得以证明。输注GM2941以剂量依赖性方式延缓了肺肉芽肿的形成。在中性粒细胞积累达到峰值时测量的全肺髓过氧化物酶活性，在预先用GM2941（30毫克/千克，24微摩尔/千克）处理的动物中显著降低，这表明该化合物至少部分地通过阻碍中性粒细胞募集提供保护。这些数据表明，GM2941对与葡聚糖输注相关的肉芽肿形成提供了显著程度的保护，可能是通过中断中性粒细胞募集实现的。
