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透明质酸(hyaluronic acid, HA)又名玻璃酸。首次在1934年由Meyer和Palmer自牛眼玻璃体内提取分离[1]。HA同样广泛存在于人体中,包括人眼的玻璃体、脐带和皮肤等组织(表1),是细胞外基质的组成部分[2]。HA化学名称为(1,4)-O-β-D葡萄糖醛酸-(1,3)-2-乙酰氨基-2-脱氧-β-D葡萄糖,是一种高分子直链聚糖,由交替的N-乙酰葡糖胺(GlcNAc)和葡糖醛酸(GlcA)双糖单位反复交替而形成的一种聚合物[3],其分子量的差别很大,分子式为(C14H20NO11Na)n,双糖单位的分子量为401.3(图1)。由于其直链的链轴L单糖之间氢键的作用,HA分子在空间呈刚性的螺旋柱型,其半径为200 nm。HA呈强亲水性,在水溶液中,HA亲和的水分约为其本身重量的1000倍。除了亲水性外,HA溶液还有着独特的流体力学性质,其水溶液是一种非牛顿型流体,因此,有着良好的黏弹性和应变性[4]。目前HA广泛应用于生物材料、药物靶向制剂、美容以及腹部手术后预防粘连等[5]。
表 1 人体不同组织中透明质酸的含量
组织或体液 HA浓度(μg/ml) 眼玻璃体 140~340 脐带 4100 关节滑液 1400~3600 真皮 200~500 表皮 100 胸淋巴液 0.2~50 尿液 0.1~0.3 血清 0.01~0.1 -
人体内HA主要由HA分解酶(Hyals)分解,其中最主要的酶是Hyal-1和Hyal-2。Hyal-2将HA降解成低分子量HA,Hyal-1将HA降解成低分子寡聚体。高分子量HA仅β1、4键暴露,降解缓慢,当HA分子量低于30万时,HA聚集能力降低,降解速度呈指数倍增加[39]。有报道[40]HA能被降解为多糖,为葡萄球菌和链球菌等提供营养。Zhang等[41]研究表明,在富含HA的培养基中,化脓性链球菌的M1蛋白、胶原样表面蛋白和糖酵解酶甘油醛-3-磷酸脱氢酶等几种致病因子上调。但是也有报道[42-43],HA能抑制SA等细菌的生长,1 mg/ml浓度时就能达到最大抑制作用,但是没有杀菌作用。高浓度高分子量HA体外抑制SA和大肠埃希菌的生长,并且体内体外均不影响抗生素的药效[28]。Jae采用小鼠盲肠结扎穿刺法,构建小鼠腹腔脓肿模型,通过腹腔注射高分子量HA(20 mg/kg),能有效的降低腹腔菌载量,降低炎症因子水平,提高小鼠的存活率[44]。
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内源性低分子量HA可以促进血管生成,增加肿瘤细胞的供血,促进肿瘤细胞的生长[45-47];另外,内源性低分子量HA也可以促进肿瘤细胞表面CD44的分泌,从而促进肿瘤细胞的转移[48]。通过抑制透明质酸合成酶3(HAS3),降低低分子量HA的产生,可使前列腺肿瘤血管生成减少70%~80%,肿瘤生长速度降低[49]。透明质酸合成酶2(HAS2)过表达,高分子量HA合成增加,组织中高分子量HA浓度升高,反而体现出抑制肿瘤细胞的生长[50]。也有文献报道,内源性的HA能促进肿瘤细胞增殖和扩散[51-53]。外源性HA根据分子量不同,应用也不同[32,54](表2)。外源性高分子量HA进入人体后会促进HAS2高表达,加速内源性高分子量HA合成,使机体高分子量HA浓度增加,从而抑制肿瘤的生长和扩散[55]。Aikaterini用外源性高分子量HA显著抑制 HT1080细胞的迁移,当加入HA分解酶水解高分子量HA后,HT1080 细胞运动性显著增加[56]。高分子量HA钠凝胶能够抑制结肠癌细胞的转移[57]。除了和抗肿瘤药物合用,外源性寡聚体HA单用还可以与CD44 受体结合,增强肿瘤细胞的凋亡[58],与HA介导的运动受体结合,降低肿瘤细胞的转移[59]。
表 2 不同相对分子质量外源性透明质酸的应用
用途 分子量(Da) 作用 骨关节注射液 >5×106 对受损部位润滑和机械保护作用; 眼科手术黏弹剂 >3×106 撑起前房,减少术后炎症的发生 滴眼液 (1~1.5)×106 增加滞留时间;润滑和保护作用 术后防黏连 >1×106 形成隔离层,抑制炎症反应 化妆品 (0.5~2)×106 保湿 抗肿瘤药载体 (5~7.5)×105 与肿瘤CD44靶点特异性结合 对创伤修复 <5×105 促进巨噬细胞的吞噬作用;促进血管形成 抗肿瘤作用 800~3200 特异性结合CD44受体和RHAMM受体
Research progress on action mechanism and clinical application of hyaluronic acid
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摘要: 透明质酸广泛存在于人体中,是细胞外基质的重要成分,具有独特的流体力学性质、良好的黏弹性和应变性。目前透明质酸被广泛用于生物材料、药物靶向制剂、美容以及腹部手术后预防黏连等。随着透明质酸应用范围的扩展及新型医用材料的不断涌现,近年来对透明质酸的研究日益增加。本文对透明质酸的临床应用及其作用机制进行综述,以期为透明质酸产品的进一步研发和安全应用提供参考。Abstract: Hyaluronic acid is widely present in the human body. It is an important component of extracellular matrix. It has unique hydrodynamic properties, good viscoelasticity and strain properties. At present, hyaluronic acid has been widely used in biomaterials, targeted-drug preparations, cosmetics and prevention of adhesion after abdominal surgery. With the expansion of the application scope of hyaluronic acid and the continuous emergence of new medical materials, the research on hyaluronic acid has been increasing in recent years. This paper reviews the clinical application of hyaluronic acid and its mechanism, in order to provide reference for the further development and safe application of hyaluronic acid products.
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表 1 人体不同组织中透明质酸的含量
组织或体液 HA浓度(μg/ml) 眼玻璃体 140~340 脐带 4100 关节滑液 1400~3600 真皮 200~500 表皮 100 胸淋巴液 0.2~50 尿液 0.1~0.3 血清 0.01~0.1 表 2 不同相对分子质量外源性透明质酸的应用
用途 分子量(Da) 作用 骨关节注射液 >5×106 对受损部位润滑和机械保护作用; 眼科手术黏弹剂 >3×106 撑起前房,减少术后炎症的发生 滴眼液 (1~1.5)×106 增加滞留时间;润滑和保护作用 术后防黏连 >1×106 形成隔离层,抑制炎症反应 化妆品 (0.5~2)×106 保湿 抗肿瘤药载体 (5~7.5)×105 与肿瘤CD44靶点特异性结合 对创伤修复 <5×105 促进巨噬细胞的吞噬作用;促进血管形成 抗肿瘤作用 800~3200 特异性结合CD44受体和RHAMM受体 -
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