Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands
Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands
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DOI：
10.1152/ajpcell.00009.2010
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发表时间：
2010-07-01
影响因子：
5.5
通讯作者：
Kennedy, Thomas P.
中科院分区：
文献类型：
--
作者：
Rao, Narayanam V.;Argyle, Brian;Kennedy, Thomas P.
Rao NV，Argyle B，Xu X，Reynolds PR，Walenga JM，Prechel M，Prestwich GD，MacArthur RB，Walters BB，Hoidal Jr，Kennedy TP。低抗凝剂肝素针对多个部位的炎症，抑制肝素诱导的血小板减少，并抑制RAGE与其配体的相互作用。Am J Physiol Cell Physiol 299：C97-C110,2010。2010年4月7日首次出版；DOI：10.1152/ajpcell.00009.2010。虽然肝素几乎只被用作血液抗凝剂，但重要的文献表明，它也具有广泛的抗炎活性。在这里，我们使用低抗凝剂2-O，3-O-脱硫肝素(ODSH)，证明了肝素的大部分抗炎药理作用与抗凝活性无关。ODSH对抗凝血酶III的亲和力低，抗Xa和抗IIa抗凝活性低，不激活Hageman因子(FXII)。与肝素不同，ODSH不与肝素诱导的血小板减少症患者中存在的肝素-血小板因子-4抗体相互作用，甚至在肝素的激活浓度存在时抑制血小板的激活。与肝素一样，ODSH抑制补体激活，与白细胞黏附分子P-选择素、白细胞阳离子颗粒蛋白天青素、人白细胞弹性蛋白酶和组织蛋白酶G结合。此外，ODSH和肝素阻断Mac-1(CD11b/CD18)介导的白细胞与晚期糖基化终产物受体(RAGE)的黏附，并抑制其许多促炎配体的RAGE连接，包括晚期糖基化终末产物羧甲基赖氨酸-牛血清白蛋白、核蛋白高迁移组盒蛋白-1(HMGB-1)和S100颗粒蛋白。在小鼠中，ODSH比肝素更有效地减少黑色素瘤的选择素介导的肺转移，并抑制气管内HMGB-1的RAGE介导的呼吸道炎症。在人体中，在没有抗凝的情况下，ODSH对这些抗炎活性的50%抑制浓度可以在血液中实现。这些结果表明，肝素的抗凝活性与其抗炎作用不同，表明可以去除2-O和3-O硫酸盐基团，在不损害其抗炎药理的情况下降低肝素的抗凝活性。
Rao NV, Argyle B, Xu X, Reynolds PR, Walenga JM, Prechel M, Prestwich GD, MacArthur RB, Walters BB, Hoidal JR, Kennedy TP. Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands. Am J Physiol Cell Physiol 299: C97-C110, 2010. First published April 7, 2010; doi:10.1152/ajpcell.00009.2010.-While heparin has been used almost exclusively as a blood anticoagulant, important literature demonstrates that it also has broad anti-inflammatory activity. Herein, using low anti-coagulant 2-O, 3-O-desulfated heparin (ODSH), we demonstrate that most of the anti-inflammatory pharmacology of heparin is unrelated to anticoagulant activity. ODSH has low affinity for anti-thrombin III, low anti-Xa, and anti-IIa anticoagulant activities and does not activate Hageman factor (factor XII). Unlike heparin, ODSH does not interact with heparin-platelet factor-4 antibodies present in patients with heparin-induced thrombocytopenia and even suppresses platelet activation in the presence of activating concentrations of heparin. Like heparin, ODSH inhibits complement activation, binding to the leukocyte adhesion molecule P-selectin, and the leukocyte cationic granular proteins azurocidin, human leukocyte elastase, and cathepsin G. In addition, ODSH and heparin disrupt Mac-1 (CD11b/CD18)-mediated leukocyte adhesion to the receptor for advanced glycation end products (RAGE) and inhibit ligation of RAGE by its many proinflammatory ligands, including the advanced glycation end-product carboxymethyl lysine-bovine serum albumin, the nuclear protein high mobility group box protein-1 (HMGB-1), and S100 calgranulins. In mice, ODSH is more effective than heparin in reducing selectin-mediated lung metastasis from melanoma and inhibits RAGE-mediated airway inflammation from intratracheal HMGB-1. In humans, 50% inhibitory concentrations of ODSH for these anti-inflammatory activities can be achieved in the blood without anticoagulation. These results demonstrate that the anticoagulant activity of heparin is distinct from its anti-inflammatory actions and indicate that 2-O and 3-O sulfate groups can be removed to reduce anticoagulant activity of heparin without impairing its anti-inflammatory pharmacology.