Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
J Cell Mol Med. 2009 Aug;13(8B):2704-12. doi: 10.1111/j.1582-4934.2009.00658.x.
Low molecular weight heparin derivatives are characterized by low anti-coagulant activity and marked anti-inflammatory effects that allow for these molecules to be viewed as a new class of non-steroidal anti-inflammatory drugs (NSAIDs). We show here that K5NOSepiLMW, an O-sulphated heparin-like semi-synthetic polymer of the D-glucuronic acid-N-acetyleparoson disaccharide unit with low molecular weight, has marked anti-inflammatory effects in a rat model of acute inflammation, the carrageenan-induced pleurisy, commonly used to test NSAID efficacy. A 30-min. pre-treatment with K5NOSepiLMW (0.1, 0.5 and 1 mg/kg b.wt., given intrapleurally) attenuated the recruitment of leucocytes in the lung tissue and the pleural exudate, inhibited the induction of inducible nitric oxide synthase and cyclooxygenase-2 (COX-2), thereby abating the generation of nitric oxide and pro-inflammatory prostaglandins such as PgE(2) and PGF(1alpha), reduced the inflammation-induced nitroxidative lung tissue injury, as shown by tissue thiobarbituric acid-reactive substances and nitrotyrosine, and blunted the local generation of cytokines such as interleukin-1beta and tumour necrosis factor-alpha. All these parameters were markedly increased by intrapleural carrageenan in the absence of any pre-treatment. The anti-inflammatory action of K5NOSepiLMW is specific, as judged by the lack of therapeutic effects of B4/110, a biologically inactive cognate polysaccharide, given in the place of the authentic molecule. Moreover, K5NOSepiLMW showed similar effects as celecoxib (1 mg/kg b.wt), a COX-2 inhibitor and well-known NSAID. This study provides further insight into the mechanisms underlying the beneficial effects of heparin derivatives in inflammation and identifies K5NOSepiLMW as a novel, promising anti-inflammatory drug.
低分子量肝素衍生物的特点是抗凝活性低，抗炎作用显著，因此可以将这些分子视为一类新型非甾体抗炎药（NSAIDs）。我们在这里展示了 K5NOSepiLMW，一种低分子量的 O-硫酸化肝素样半合成聚合物，由 D-葡萄糖醛酸-N-乙酰基帕罗松二糖单元组成，在角叉菜胶诱导的胸膜炎大鼠急性炎症模型中具有显著的抗炎作用，该模型常用于测试 NSAID 的疗效。在给予 K5NOSepiLMW（0.1、0.5 和 1 mg/kg b.wt.，腹腔内给药）30 分钟预处理后，可减轻肺组织和胸腔渗出液中白细胞的募集，抑制诱导型一氧化氮合酶和环氧化酶-2（COX-2）的诱导，从而减少一氧化氮和促炎前列腺素如 PgE（2）和 PGF（1alpha）的产生，减轻炎症引起的氮氧自由基肺组织损伤，如组织硫代巴比妥酸反应物质和硝基酪氨酸所示，并减轻细胞因子如白细胞介素-1β和肿瘤坏死因子-α的局部产生。所有这些参数在没有任何预处理的情况下，通过腹腔内角叉菜胶明显增加。K5NOSepiLMW 的抗炎作用是特异性的，因为在给予与真实分子同源但无生物活性的 B4/110 多糖的情况下，没有治疗效果。此外，K5NOSepiLMW 表现出与塞来昔布（1 mg/kg b.wt.）相似的效果，塞来昔布是一种 COX-2 抑制剂和著名的 NSAID。这项研究进一步深入了解肝素衍生物在炎症中的有益作用的机制，并确定 K5NOSepiLMW 为一种新型有前途的抗炎药物。
