Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation
Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation
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DOI：
10.1073/pnas.1003103107
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发表时间：
2010-11-16
影响因子：
11.1
通讯作者：
Haag, Rainer
中科院分区：
文献类型：
--
作者：
Dernedde, Jens;Rausch, Alexandra;Haag, Rainer
白细胞与内皮细胞的黏附作用启动了白细胞向炎症组织的迁移，对免疫监测具有重要意义。急性和慢性炎症性疾病表现为免疫反应失调，并导致大量白细胞外流，从而导致进一步的组织损伤。因此，针对白细胞贩运可能提供一种有效的抗炎疗法。白细胞迁移是由细胞黏附分子E-、L-和P-选择素及其相应的碳水化合物配体相互作用而启动的。因此，有效解决这些相互作用的化合物具有很高的治疗价值。基于这一原理，我们研究了合成树枝状聚甘油硫酸酯(DPGS)作为大分子抑制剂，它通过模仿自然产生的配体的多价结合机制起作用。DPGS对白细胞L-选择素和内皮P-选择素均有高效抑制作用。聚合物核的大小和硫酸盐化程度决定了选择素的结合亲和力。在接触性皮炎小鼠模型中，给予dPGS与糖皮质激素一样有效地抑制了白细胞的外渗，并显着减少了水肿的形成。此外，dPGS在体外与补体因子C3和C5相互作用，并在补体激活的小鼠模型中降低C5a水平。因此，dPGS代表了一种可用于治疗炎症性疾病的全合成聚合物疗法的创新类别。
Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of anti-inflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.