Advances in Clinical Medicine
Vol. 12  No. 06 ( 2022 ), Article ID: 52756 , 9 pages
10.12677/ACM.2022.126817

硫酸软骨素生物学功能及其在疾病治疗中的 作用

栾军杰1,2,田雪1,2,张晓晖3,彭旭东2*

1青岛大学,山东 青岛

2青岛大学附属医院,山东 青岛

3安丘市人民医院,山东 潍坊

收稿日期:2022年5月21日;录用日期:2022年6月11日;发布日期:2022年6月23日

摘要

硫酸软骨素(chondroitin sulfate)是天然存在的酸性粘多糖,具有免疫调节、促进伤口愈合、抗病毒作用、抗氧化及调控肿瘤生长等多种药理和生物学活性,并已被广泛用于治疗炎症相关性疾病。此外,还可以作为生物材料应用于医学领域,本综述总结了硫酸软骨素的各种生物学功能及其在疾病治疗中的作用,为进一步临床应用提供了参考。

关键词

硫酸软骨素,生物学功能,免疫调节,疾病治疗

The Biological Function of Chondroitin Sulfate and Its Role in Disease Treatment

Junjie Luan1,2, Xue Tian1,2, Xiaohui Zhang3, Xudong Peng2*

1Qingdao University, Qingdao Shandong

2The Affiliated Hospital of Qingdao University, Qingdao Shandong

3Anqiu People’s Hospital, Weifang Shandong

Received: May 21st, 2022; accepted: Jun. 11th, 2022; published: Jun. 23rd, 2022

ABSTRACT

Chondroitin sulfate is a naturally acidic mucopolysaccharide. It has various pharmacological effects and biological activities, such as immunomodulation, promotion of wound healing, antiviral effect, antioxidant and tumor growth regulation. It has been widely used in the treatment of inflammation related diseases. In addition, it can also be used as a biomaterial in the medical field. This review summarizes the various biological functions of chondroitin sulfate and its role in disease treatment, providing a reference for further clinical applications.

Keywords:Chondroitin Sulfate, Biological Functions, Immunomodulatory, Disease Treatment

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

硫酸软骨素(chondroitin sulfate, CS)是由葡糖醛酸和N-乙酰氨基半乳糖连接而成的重复双糖,硫酸基团可以基于不同的位置进而对其分子结构进行修饰 [1] [2],使其具有多样化的药理和生物活性。CS广泛存在于细胞外基质,尤其是在软骨、皮肤、血管、韧带和肌腱中,它是蛋白聚糖的重要组成部分 [3],通常与膜蛋白连接形成CS蛋白聚糖分布在几乎所有细胞表面。首先,CS具有抗炎 [4] [5] [6]、免疫调节 [7]、促进伤口愈合 [8]、抗凝血及血栓 [9]、调控肿瘤生长 [10] [11]、保护软骨 [12] [13]、抗病毒 [14]、抗氧化 [15] [16]、细胞黏附调节 [17]、止痛 [18] 等多种药理和生物学活性。目前CS已经作为治疗与关节疼痛相关的治疗药物之一,并且被广泛应用于骨关节炎的治疗 [5],其次,由于CS多价性以及强大的可设计性等分子结构特点 [19],目前已成为研究聚合物科研人员的关注焦点。CS因具有丰富且易于调节生物功能,生物可降解性,生物相容性良好,易于化学修饰,粘附性能良好,无免疫反应等特点被应用于药物输送及组织工程 [20],通过这种方式可以将药物等嵌入到生物材料,从而达到定点输送、定点缓释,在减少药物毒副作用的同时,有效地提高药学功能,并在避免宿主免疫排斥风险等方面发挥优势 [21]。当然,CS长期服用毒副作用小也是不可忽视的优势,是极具开发潜力的药物。

2. 来源及理化性质

CS是从动物(猪,牛,鸡,鲨鱼等)的软骨中提取的酸性粘多糖 [22],呈无味的白色粉末状,易溶于水,不溶于乙醚等有机溶剂,有较好的热稳定性。CS是由葡糖醛酸和N-乙酰氨基半乳糖连接的双糖,可由1,4糖苷键进一步连接成为多糖。化学结构如图1

Figure 1. Chemical structure of CS

图1. CS的化学结构式

3. 免疫调节作用

3.1. 抗炎作用

目前在多种动物和细胞炎症相关疾病模型中研究证实CS可以发挥良好的抗炎作用。在炎症反应过程中,NF-κB与靶基因启动子的结合增强促炎因子的释放,环氧合酶2 (COX-2),磷脂酶A2和基质金属蛋白酶等的表达,这些蛋白质会损害组织并促进炎症反应。NF-κB的激活在免疫稳态和炎症反应中具有关键作用,在骨关节炎的疾病模型中,CS可以减少软骨细胞和滑膜中的NF-κB活化和核易位,进而发挥抗炎作用 [23]。在骨关节炎发病过程中,促炎细胞因子(IL-1β和TNF-α)、具有蛋白水解活性的酶(MMPs)和具有促炎活性的酶(COX-2和NOS-2)的增加可继发关节损伤和滑膜炎。这些蛋白质在软骨细胞和滑膜中的表达增强与NF-κB的激活和核转位有关,研究证实,在骨关节炎中CS可以通过抑制细胞外ERK1/2和p38MAPK的激活,进而减少NF-κB的核易位,从而起到抗炎作用 [24] [25]。与之相一致地,Claudia Jomphe等 [25] 使用从雄性新西兰白兔膝盖的双侧关节处无菌收集的软骨细胞作为研究对象,证实CS减少了IL-1β诱导的p38MAPK和Erk1/2磷酸化以及NF-κB核易位。不仅如此,在大鼠急性骨关节炎症的实验模型中,使用CS对大鼠进行预防性和治疗性给药后,血清中促炎细胞因子IL-1β,IL-12B p40,TNF-α的浓度明显降低 [26]。在小鼠II型胶原(CII)诱导的关节炎(CIA)模型中,CS以剂量依赖性方式降低关节炎指数和血清抗CII抗体滴度,进而发挥抗炎作用 [27]。此外,由脂多糖(LPS)介导的TLR-4复合物的激活可诱导特定的信号通路,如MyD88和TRAF-6,可以引发NF-κB激活,在小鼠软骨细胞体外实验的研究表明,CS显着降低了MyD88、TRAF-6、NF-κB的表达,进而起到了抗炎的作用 [28]。在间质性膀胱炎大鼠模型中,CS的治疗降低了肥大细胞和白细胞的数量、血管充血和粘膜下水肿的程度以及膀胱肉芽肿的分级,进而起到改善尿路上皮的疗效 [4]。近年研究还报道了CS对单核、巨噬细胞的抗炎作用,Stabler等人 [29] 表明CS可作为人单核细胞THP-1中NK-κB活化的有效抑制剂,而Taraballi等人 [3] 证实CS阻断LPS与CD44在大鼠骨髓源性巨噬细胞上的结合,从而抑制LPS/CD44/NF-κB级联反应。综上,CS是一种安全有效的抗炎药物且有广泛的应用前景。

3.2. 抗过敏作用

I型过敏反应的机制包括抗原特异性IgE的产生,嗜碱性粒细胞或肥大细胞上的免疫球蛋白Fc段受体可与产生的IgE 相结合,IgE与新吸收的过敏原交联,以及从细胞中释放化学介质,例如组胺和白三烯。在以卵清蛋白(OVA)致敏的小鼠模型中,CS治疗组可以减少DNP-OVA的特异性IgE和IgG1产生,此项实验的研究结果表明,CS通过下调辅助性T细胞反应和上调调控性T细胞的分化,进而下调小鼠的Th2反应来抑制IgE介导的过敏反应 [30]。此外,研究发现,在OVA致敏BALB/c小鼠脾细胞体外模型中,CS处理组细胞体外模型Th1型细胞因子(IFN-g、IL-2和IL-12)分泌上调,Th2型细胞因子(IL-5和IL-10)的分泌下调,首次证实CS可以通过调控Th1细胞分泌细胞因子,进而减少抗原诱导的IgE产生,这一发现提示了CS在预防IgE介导的过敏方面的潜在应用 [31] [32]。

4. 在眼科疾病治疗中的作用

干眼症被认为是最常见的眼科疾病之一 [33]。Llamas-Moreno等 [34] 研究发现CS/黄原胶(CS/XG)治疗干眼症在延长泪膜破裂时间方面与思然滴眼液有同样的效果,与此同时CS/XG组的治疗组可以更有效的减少眼表疾病指数。泪膜不稳定性与角膜干燥引起的角膜上皮损伤密切相关,Hirai等 [35] 建立角膜地形图模型系统分析兔泪膜稳定性,研究表明通过局部滴注0.1%的透明质酸(HA)和1.0% CS对治疗干眼症患者的泪膜不稳定有效。Liu等 [36] 研发了一种新型的胶原–硫酸软骨素膜,该膜具有较高的保湿能力,不仅可以促进角膜修复、降低患干眼症的风险,而且可以提高临床角膜移植成功率,在角膜疾病治疗中具有潜在的用途。在人工角膜研发过程中,角膜中不同类型细胞的共培养能力至关重要。研究发现,胶原–硫酸软骨素支架具有优良的共培养能力、良好的弹力等特性,并且符合药物毒理学和药物安全性的要求,是构建人工角膜的良好基质 [37]。在新型眼部给药制剂研究中发现,负载于CS与泊洛沙姆的接枝共聚物中的环丙沙星可以在眼表持续释放,达到良好药物缓释效果,是一种优良的药物载体 [38]。粘弹剂作为现代白内障手术中不可或缺的手术器械,一项前瞻性随机临床试验研究发现,在超声乳化术中使用由1.6% HA和4.0% CS组成的粘弹剂角膜内皮细胞计数显著高于使用2.0%羟丙基甲基纤维素的粘弹剂后,证明使用HA/CS组成的粘弹剂可以提高角膜内皮的保护水平 [39]。此外,Strehin等 [40] 研究发现,CS-聚乙二醇(CS-PEG)粘弹剂与角膜细胞具有细胞相容性,能够密封200 mmHg及更高眼压下的全层角膜切口,并且可生物降解,使炎症反应最小化,抵抗上皮细胞向内生长,且不会诱导瘢痕形成。在角膜移植手术中,供体角膜的良好保存是手术成功的重要保障,Bourne等人 [41] 研究指出,以CS为基础的保存介质可以有效地延长供者角膜的保存时间,为供体角膜提供良好的保存条件。此外,在角膜损伤的模型中研究发现,CS还可以通过为细胞移行提供构架,促进角膜上皮细胞的移行,进而加速角膜的创伤的愈合 [42]。

5. 促进伤口愈合的作用

成纤维细胞在肉芽组织中的粘附是伤口愈合的重要过程。研究证实,CS促进成纤维细胞增殖,这种活性依赖于硫酸基团的存在。以兔为模型生物,研究CS对腭成纤维细胞增殖、粘连和迁移的影响 [43],结果证实CS通过调节成纤维细胞黏附、细胞增殖和细胞迁移在腭部创面愈合中发挥重要作用 [17]。还有研究表明CS可以通过促进上皮再生和成纤维细胞增殖来加速鼻窦黏膜的伤口愈合 [8],在伤口愈合过程中起到积极作用。

6. 抗凝血及血栓的作用

CS是天然存在的酸性黏多糖 [2],与肝素的化学结构十分相似。与肝素不同,CS可以通过纤维蛋白原系统发挥抗凝血作用。研究证实,在在氯化亚铁致大鼠动脉损伤模型中,使用过氧化氢酶(CAT)治疗与经过CS修饰后的过氧化氢酶(CAT-CHS)治疗相比较,共轭物CAT-CHS的抗血栓活性增强,共轭物CAT-CHS在动脉闭塞的减速和预防方面更有效 [9]。Paulo等 [44] 通过实验证实具有硫酸化岩藻糖侧链的CS (FucCS)不仅可以通过影响肝素辅因子II发挥作用,还可以影响凝血酶的产生,进而起到抗凝作用。此外,用凝血活素刺激外源性凝血通路,研究了从海参中提取的FucCs的抗血栓作用,实验结果证实FucCs相较低分子肝素和硫酸皮肤素的抗凝作用更明显 [45]。

7. 调控肿瘤生长的作用

CS广泛存在于细胞表面和细胞外基质,根据CS硫酸基团修饰的差异可将其分为CS-A,CS-B,CS-C,CS-D,CS-E。正常细胞中大都以CS-A二糖的形式存在,然而在恶性肿瘤细胞中CS-A二糖的含量显著下降,无硫酸化的CS和CS-C的含量有明显的上升趋势。关于CS在肿瘤生长的调控作用,Pudelko等 [11] 研究并提出在肿瘤的进展和转移中CS-C可能存在双重影响。但值得肯定是的,从鲟鱼提取的CS(SCS)在体外能显著抑制结肠癌细胞株HCT-116的增殖并诱导其凋亡。同时,SCS可抑制细胞增殖、激活线粒体凋亡级联反应诱导细胞凋亡,进而对肿瘤的生长起到抑制作用。因此,SCS可作为大肠癌预防和治疗的潜在候选药物 [10]。此外,外源性CS-E通过竞争机制干扰癌细胞自身的CS-E与正常组织高亲和性受体结合而发挥抑制肿瘤生长的作用 [46]。外源CS的摄入也可以发挥治疗癌症的功能,其作用机制是通过影响角化细胞生长因子(KGF-7)、人肝素结合表皮生长因子(HB-EGF)、血管内皮生长因子(VEGF)、血小板源性生长因子(PDGF)、转化生长因子β (TGF-β)等相关蛋白细胞因子的活性 [47]。

8. 在生物材料领域的作用

CS的多价性以及强大的可设计性的分子结构以及具有生物可降解性,生物相容性良好,粘附性能良好,无免疫反应等特点被充分地应用于生物材料领域。在眼科相关领域的生物材料学研究中,Zorzi等 [48] 使用CS与阳离子明胶杂化纳米颗粒并装载基因片段,使其免受DNase I降解,证明聚阴离子CS的加入降低纳米颗粒对人角膜细胞的体外毒性,而不会影响转染效率,是开发用于眼部治疗的更安全和更有效的纳米药物的潜在候选者。在乳腺癌的相关研究中证实,制备具有荧光标记功能的CS纳米胶囊并装载难溶性药物塞来昔布和厚朴酚可有效地用于乳腺癌的治疗 [49]。不仅如此,Pezeshki-Modaress等 [50] 制备经过CS改良的GEL-CS纳米纤维支架,使纳米纤维支架具有稳定性和高孔隙率,并且与更天然ECM结构更为近似,这为人成纤维细胞在支架上附着提供更为有利的条件。此外,研究表明以CS-A为主的水凝胶,对神经营养因子和抗炎因子有募集作用,并可以促进神经干细胞生长 [51]。此外,有研究将CS制备成为水凝胶外壳,对药物的核心粒子进行包裹,研制成靶向CD44的药物输送系统,药物被特定细胞摄取后,由于CS水凝胶壳的分解,有效载荷的药物分子会大量释放,并且具有协同作用的游离药物分子迅速诱导了肿瘤特异性细胞毒性,在此过程中纳米颗粒的内芯在抗药性肿瘤细胞中持续缓释药物分子,以保持有效的药物浓度,显著增强药物对肿瘤的抑制作用 [52]。

9. 其他作用

研究发现,CS还有其他多种药理活性。CS在戊四唑诱发的点燃性癫痫和毛果芸香碱诱发的小鼠癫痫持续状态中具有抗癫痫潜力,作为减轻和预防癫痫发作的药物 [53]。CS-E通过吸附抑制登革热病毒(DENV)感染细胞并且显著降低了所有登革病毒血清型对BHK-21和Vero细胞的感染性,进而起到抗病毒的作用 [54]。CS功能化支架CSS不仅显示出适当的可逆压缩性和机械性能,而且还显示出适当的生物相容性,从而使细胞增殖,可以表现出促进软骨再生特性 [55]。在STZ诱导的糖尿病大鼠模型中,CS可以有效预防糖尿病引起的骨质流失 [56]。体外角膜器官培养模型与体外角膜上皮单层培养模型中,CS可以抑制白念珠菌孢子的粘附 [57]。在CCl4诱导的大鼠肝细胞模型中,通过测量SOD、CAT等来评价微粒体部分的脂质过氧化,结果显示,CS可能是CCl4诱导的大鼠肝细胞脂质过氧化引起的氧化应激中自由基的潜在清除者,进而起到抗氧化的作用 [58]。此外CS在治疗慢性腰痛 [59]、保护和修复神经元 [60]、调脂降脂 [61]、抗动脉粥样硬化 [62]、治疗银屑病 [63]、调节细胞黏附 [17] 等方面皆发挥一定的生物学功能。

10. 总结与展望

CS作为天然存在的糖胺聚糖,由于其生物活性广泛且化学可修饰性强,目前在CS的药理作用研究及其在生物材料领域中的应用已取得巨大进展。CS的主要的药理活性有免疫调节,促进伤口愈合,抗凝抗血栓,抗氧化,抗病毒等,并在调控肿瘤的生长,减轻和预防癫痫发作,调脂降脂,抗动脉粥样硬化等方面发挥重要的作用。CS强大的化学可修饰性,使CS作为水凝胶、纳米颗粒、纳米胶囊、纳米纤维支架、细胞支架等重要的成分被广泛研究。CS的这些生物学活性及其作为生物材料的应用已被大量体内外实验所验证,其相关临床实验特别是临床类药物治疗实验还有极大的发展空间。目前,CS在干眼的治疗以及眼科新型给药制剂方面的研究已取得进展,但是,在眼科疾病治疗中,CS免疫调节方面的作用及其机制尚未明确,我们需要在体外实验和动物实验支持的基础上,进一步着力进行药物在眼科免疫调节方面的作用及其机制的研究,为完善CS在临床各领域的应用奠定坚实的基础。

文章引用

栾军杰,田 雪,张晓晖,彭旭东. 硫酸软骨素生物学功能及其在疾病治疗中的作用
The Biological Function of Chondroitin Sulfate and Its Role in Disease Treatment[J]. 临床医学进展, 2022, 12(06): 5651-5659. https://doi.org/10.12677/ACM.2022.126817

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  64. NOTES

    *通讯作者Email: doctorpxd@126.com

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