Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins.
Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins.
复制标题
肝素的抗炎作用需要氨基葡萄糖 6-O-硫酸化，并通过 L-和 P-选择素的阻断介导。
DOI：
10.1172/jci14996
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Esko,JeffreyD
中科院分区：
文献类型：
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作者：
Wang,Lianchun;Brown,JillianR;Varki,Ajit;Esko,JeffreyD
肝素在临床上作为一种抗凝血和抗血栓药物已经使用了60多年。在这里，我们表明肝素的有效抗炎特性主要是由于阻断p -选择素和l -选择素。未分离的肝素和化学修饰的类似物被测试为选择素与固定化唾液的结合抑制剂和细胞与固定化选择素或凝血酶激活的内皮细胞的粘附抑制剂。与未分离的肝素相比，改性后的肝素具有抑制活性的顺序为：过o -硫酸化肝素>肝素> 2-O，3- o -去硫≥N-去硫/N-乙酰化肝素≥羧基还原肝素≥N-，2-O，3- o -去硫肝素>> 6- o -去硫肝素。肝素在抑制巯基乙酸盐引起的腹膜炎和恶唑酮引起的延迟型超敏反应方面也表现出类似的差异。缺乏P-或l -选择素的小鼠表现出炎症受损，肝素可以进一步减轻炎症。然而，肝素对缺乏P-和l -选择素的小鼠没有额外的作用。我们得出结论：(a)肝素的抗炎作用主要是通过阻断P-和l -选择素引发的细胞粘附介导的；(b)葡萄糖胺残基上C6处的硫酸盐基团在抑制选择素中起关键作用；(c)一些非抗凝形式的肝素保留抗炎活性。这些类似物可能被证明是治疗上有效的炎症抑制剂。
Heparin has been used clinically as an anticoagulant and antithrombotic agent for over 60 years. Here we show that the potent anti-inflammatory property of heparin results primarily from blockade of P-selectin and L-selectin. Unfractionated heparin and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl LewisXand of cell adhesion to immobilized selectins or thrombin-activated endothelial cells. Compared with unfractionated heparin, the modified heparinoids had inhibitory activity in this general order: over–O-sulfated heparin > heparin > 2-O,3-O-desulfated ≥N-desulfated/N-acetylated heparin ≥ carboxyl-reduced heparin ≥N-,2-O,3-O-desulfated heparin >> 6-O-desulfated heparin. The heparinoids also showed similar differences in their ability to inhibit thioglycollate-induced peritonitis and oxazolone-induced delayed-type hypersensitivity. Mice deficient in P- or L-selectins showed impaired inflammation, which could be further reduced by heparin. However, heparin had no additional effect in mice deficient in both P- and L-selectins. We conclude that (a) heparin’s anti-inflammatory effects are mainly mediated by blocking P- and L-selectin–initiated cell adhesion; (b) the sulfate groups at C6 on the glucosamine residues play a critical role in selectin inhibition; and (c) some non-anticoagulant forms of heparin retain anti-inflammatory activity. Such analogs may prove useful as therapeutically effective inhibitors of inflammation.