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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 Sep 28;48(9):1411–1418. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.230092

义齿性口腔炎的发病机制和防治

Pathogenesis and preventions of denture stomatitis

YANG Fenghui 1,2,3,2, YANG Yuanchao 1,2, LIN Mengwei 1,2, HE Xinyi 1,2, YANG Yan 1,2,✉
Editor: 田 朴
PMCID: PMC10929865  PMID: 38044653

Abstract

Denture stomatitis (DS) is one of the frequent oral diseases caused by multiple factors among denture wearers and is an erythematous lesion of the mucosa in the denture-bearing area, which is a limited and non-specific damage that seriously endangers the oral health of denture wearers. Traditional drug treatment for DS is effective, but it is prone to the development of drug-resistant strains. Therefore, it is important to find new treating options. For the prevention and treatment of DS, there are various methods such as direct administration of azole and polyene antibiotics to the mucosal lesions, extra-oral cleaning of the denture by cleansers and physical disinfection, and modification of denture materials. Natural ingredient preparations that have emerged in recent years are safe, convenient, inexpensive, and less likely to produce drug-resistant strains, and are seen as new sources of drugs for DS treatment. Photodynamic therapy has shown superior antibacterial properties and is also considered promising due to the convenience and safety of the treatment process and the ease of developing drug resistance. Antibacterial agents endow dentures with new characteristics, and denture modification will be a new way to treat DS. In addition, combining different prevention and control methods has shown better antibacterial activity against Candida albicans, which also provides new ideas for prevention and treatment of DS in the future.

Keywords: denture stomatitis, Candida albicans, denture modified, natural extract, combined medication

义齿性口腔炎(denture stomatitis，DS)是一种发生于活动义齿基托承托区黏膜的局限性、非特异性损害，主要表现为红斑性病变，24%~60%的佩戴者受其困扰[1]。DS是一种多因素疾病，其主要病原菌为白色念珠菌，随着抗生素和皮质类固醇激素等药物的滥用，患者感染念珠菌的概率日渐增大[2]。此外，创伤、口腔卫生不良、糖类摄入高、唾液流量减少、年龄、抽烟等也是DS形成的重要因素[3]。

针对不同的致病因素有不同的治疗方法，如采用抗真菌药物和糖皮质激素等进行全身或局部治疗，以及义齿清洁剂结合物理消毒的口外处理。天然提取物表现出毒性小，不易使病原菌产生耐药的特性，逐渐受到关注。义齿作为白色念珠菌最主要的定植区，对其材料进行改性成为预防DS的重要手段。本文对近5年DS的发病机制及防治方法的研究进展，尤其是天然提取物及材料改性方面进行综述，以期为DS的防治研究和临床治疗提供参考。

1. 发病机制

白色念珠菌是口腔中的常见病原菌，一般情况下，与其他细菌拮抗共生，不表现致病性。当微环境发生改变时，白色念珠菌可由酵母相转换为假菌丝相，毒力和侵袭力增强，诱发DS。菌群失调、放射治疗、营养摄入不均衡及系统性疾病等都是造成微环境改变的因素[4]。DS表现为全口或局部活动义齿区域的黏膜炎症，更常见于全口义齿，与义齿材料相关。义齿材料的多孔结构可增加表面粗糙度，为白色念珠菌黏附定植创造条件，促进生物膜的形成[5]。当义齿区域黏膜发生病变或创伤时，病原体更容易侵入受损部位，引起感染。

白色念珠菌黏附是致病的首要步骤，主要是通过菌体表面的糖蛋白类物质，如甘露聚糖-蛋白质复合物、几丁质及黏附素等与宿主细胞的糖蛋白受体相结合[6]。其中，凝集素样序列蛋白3(agglutinin-like sequence 3 protein，Als3p)与菌丝壁蛋白1(hyphal wall protein 1，Hwp1)为白色念珠菌黏附过程中关键的黏附素，与生物膜的形成密切相关，二者在念珠菌感染的发病机制中存在协同作用[7]。

菌丝生成是白色念珠菌侵袭的关键步骤，菌丝上表达的溶酶类和侵入素结合，可以降解E-钙黏蛋白和其他上皮间细胞连接蛋白，使菌丝能够穿透上皮细胞[8]。Als3不仅介导黏附过程，还是重要的侵袭因子。它通过诱导宿主细胞骨架重排触发宿主细胞的内吞作用[9]。白色念珠菌进入宿主细胞后，产生延伸菌丝穿透细胞入侵组织，最终导致宿主细胞膜被破坏。

机体在抵御白色念珠菌的侵袭过程中，黏膜固有免疫在宿主维持念珠菌共生中起核心作用[8]。家族、C型凝集素受体超家族共同促进固有免疫细胞对真菌的清除，Mincle调节细胞因子的产生，促进炎症和免疫过程[10-13]。适应性免疫与固有免疫信号通路交联，可为宿主提供长期的保护作用。B淋巴细胞可以直接识别白色念珠菌菌丝和酵母多糖，或通过Toll样受体2触发的MyD88信号激活B细胞增殖分化，引起抗体分泌，最终将病原菌清除，并对白色念珠菌保持长期监控[14]。免疫细胞通过多种途径激活机体对真菌的免疫应答，当免疫系统受损或缺陷时，均可能导致DS的病程加重。

2. 防治方法

DS的病程较为复杂，在治疗时可以从抑制白色念珠菌黏附、侵袭细胞，增强机体抵抗力等方面入手，并以此为依据制定合理的治疗方案，以期能够彻底治愈DS。

DS是多种因素导致的疾病，其治疗方法也需从不同方面切入。抗生素类药物较早用于治疗真菌感染，但是随着耐药菌株的频繁出现，需要探寻新的治疗方法。义齿清洁剂用于口外清洁，当联合紫外线照射等物理方法时，能更彻底清除义齿表面病原菌。天然提取物和激光治疗以其不易使病原菌产生耐药的优势为治疗DS提供新的视角。对义齿材料进行改良，可有效抑制病原菌的黏附。这些新治疗方法的出现为DS的治疗带来新的可能。

2.1. 抗真菌药物

作为治疗DS的直接用药，传统抗真菌药物如唑类、多烯类和棘白菌素类在临床中的应用较广。以上药物的药理相近，主要针对真菌细胞膜中的麦角甾醇或真菌细胞壁中的β-(1,3)-D-葡聚糖。

唑类化合物是一种含有芳香结构的氮杂环化合物，表现出广泛的生物活性。咪康唑为典型二唑类药物，被多次证明用于治疗DS是有效且安全的，但长期使用会使病原菌产生耐药，容易导致复发[15]。泊沙康唑和伏立康唑为新一代三唑类抗真菌药物，相较于二唑类药物，对耐药菌株也表现出很高的活性，可作为治疗耐药性念珠菌病或复发性念珠菌病的有效药物[16]。

制霉菌素和两性霉素B均为多烯类药物，可有效改善DS患者的症状，但不能彻底清除白色念珠菌，停药后易复发[17]。制霉菌素对白色念珠菌的抑制作用优于两性霉素B，两者均优于氟康唑[18]。棘白菌素对不同形式的白色念珠菌均具有良好的抗菌活性，且具有快速杀真菌作用，已获批用于临床治疗念珠菌感染。白色念珠菌形成生物膜后，对唑类药物表现出高度耐药性，其次是多烯类药物，而对棘白菌素反应敏感[19]。当多烯类和唑类药物治疗失败时，棘白菌素可用于替代治疗。

传统抗真菌药物的长期使用，导致耐药菌株频繁出现，药效降低。制霉菌素联合激光治疗能显著提高治疗DS的疗效，提示联合疗法能提高传统药物的抗菌活性[20]。

2.2. 天然提取物

研究[21]表明：一些中草药和天然活性化合物具有抗菌、抗病毒和抗真菌的作用，这些天然物质可能成为抗真菌药物的新来源。同时，天然抗真菌剂还具有安全、方便、廉价的特点。

绿茶提取物与制霉菌素具有相似的抗念珠菌活性，可考虑作为新药来源[1]。芦荟提取物能抑制白色念珠菌增殖和菌丝生长而表现出抗菌活性，其牙膏制品对白色念珠菌有明显的抑制作用[22-23]。迷迭香精油通过抑制磷脂酶的产生，降低白色念珠菌的毒力，显著减少义齿表面上附着的菌落数量，具有良好的抗菌性能[24-25]。牛至精油与迷迭香精油作用相似，也可抑制磷脂酶的产生[26]。肉桂是从肉桂树皮中提取的一种物质，其主要成分是肉桂醛，对白色念珠菌细胞壁的β-(1,3)-D-葡聚糖和几丁质合成有抑制作用，还能增强上皮屏障功能，并发挥抗炎作用[27-29]。此外，百日草、丁香油、橄榄树精油、蓖麻油、茉莉花精油和蒲公英精油等都表现出对白色念珠菌有良好的抑制作用[24-25, 30-31]。

天然蜂胶具有抗菌和促进伤口愈合的特性，能改善DS患者腭水肿和红斑症状，治疗效果与咪康唑相当[32]。壳聚糖具有优良的生物相容性和抗菌性，其抗菌性能取决于分子量、去乙酰化程度以及微生物的类型[33]。壳聚糖对抑制白色念珠菌生物膜的形成有很好的作用，其中低分子量壳聚糖抑制效果最好，高分子量水溶性壳聚糖所提供的固位力足以用作义齿黏合剂，是一种理想的义齿黏合剂代替材料[34-35]。

天然杀菌剂相较于传统抗真菌药物，有较少的不良反应而更能为患者所接受，具有良好的应用前景。然而，由于提取物常为混合物，分离活性物质困难，其抑菌活性仍需要大量研究来验证，并探讨出规范的给药体系。

2.3. 激光治疗

激光技术已成为临床治疗的有效手段，具备对组织损害小，疼痛少、不良反应少等优点。目前临床上常用于治疗白色念珠菌感染的有以铒钇铝石榴石激光(Erbium:yttrium aluminum garnet laser，Er:YAG)、掺钕钇铝石榴石激光(neodymium-doped yttrium aluminium garnet lasers，Nd:YAG)和铒铬钇钪镓石榴石激光(erbium，chromium: yttrium scandium galliumgarnet laser，Er，Cr:YSGG)为代表的固体激光器，二极管半导体激光器和砷铝镓半导体激光器，临床上常用的激光治疗则属于气体激光器。

Nd:YAG、Er:YAG和Er，Cr:YSGG均属于水激光，其使用波长和频率与水的吸收峰值相近，故水分子可吸收激光能量，成为含有一定能量的水，在光照部位引发爆裂从而造成一定损伤。在2 940 nm、10 Hz、18.9 J/cm2条件下的Er:YAG对白色念珠菌的杀伤效果与氯已定相当，相同条件下100 mJ的Er:YAG激光能完全清除白色念珠菌，可考虑用作代替治疗[36-37]。Er:YAG(2 940 nm、0.3 W、15 Hz、50 μsec)和Cr:YSGG(2 790 nm、1.25 W、15 Hz、200 μsec)均能显著抑制白色念珠菌生长，相较之下，Cr:YSGG效果更好[38]。低强度(0.25 W、10 Hz、15 s、3 J)和高强度(1 W、10 Hz、60 s、59 J)的Nd:YAG激光均可不同程度地抑制白色念珠菌生长，抑制程度为10%~60%，抑制效果则不明显[39]。

砷化镓铝激光器(660 nm、35 mW、26 J/cm2)照射白色念珠菌可抑制其生长，在660 nm、35 mW、3.93 J/cm2条件下照射后，白色念珠菌相关基因的表达不同程度地下调[40-41]。在810 nm、353.7 W/cm2条件下的二极管半导体激光器能显著抑制白色念珠菌的定植，在940 nm、2 W条件下也能抑制白色念珠菌生长，但抑制效果不及Er:YAG(2 940 nm、100 mJ、10 Hz)。

气体激光器是临床上常用的治疗手段，激光治疗是一种依靠特定波长光源照射激活光敏剂，从而产生具有生物毒性的单态氧等活性氧物质，并对病原菌造成损伤，诱导其死亡的消毒方式，被认为是一种很有前途的代替疗法。血卟啉衍生物为第一代光敏剂，介导激光治疗对义齿表面的清除效果与浸泡在0.12%氯已定(chlorhexidine，CHX)中相当，优于过硼酸钠酶和柠檬酸[42]。光二噻嗪(photodithazine，PTD)在660 nm、50 J/cm2光照条件下，清除总微生物群数量上效果优于制霉菌素，在亚致死量光照强度(18 J/cm2)下，连续照射4次能够彻底清除白色念珠菌，与姜黄素(450 nm)相当[43-44]。用过氧化氢或脱氧核糖核酸酶I(DNaseI)预处理后可以提高PDT介导激光治疗的抗菌效果，且降低白色念珠菌胞外基质的含量[45-46]。另外，吲哚青绿、亚甲基蓝和钌(II)配合物等也可作为光敏剂介导激光治疗从而治疗DS[20, 44, 47-51]。

激光器在治疗DS中具有应用前景，但如何制定出一份合理安全的治疗方案还需进一步研究。

2.4. 口外清洁/消毒

白色念珠菌黏附和定植于义齿表面是DS发病的首要步骤，对义齿的彻底清洁是防治DS的一种重要手段，从义齿表面清除白色念珠菌比从黏膜上清除更容易治愈DS[52]。

义齿清洁剂能有效清除义齿表面病原菌，保持义齿表面相对无菌。常用于口外义齿清洁的成分有活性氯化物、CHX及硼酸等。

活性氯化物包括次氯酸及其钠盐、氯胺-T(chloramine T，CAT)、一氯胺等。活性氯化物对去除白色念珠菌生物膜以及DS患者病情缓解有一定疗效。CAT对游离型和生物膜型白色念珠菌均表现出持续的抑制作用，并与浓度呈正相关[53]。CHX对包括念珠菌在内的多种微生物具有抑制活性，且强于氟康唑和制霉菌素[54]。硼酸通过降低细胞麦角甾醇的合成及药物外排泵相关基因的表达来抑制白色念珠菌菌丝生长，与三氯生和氧化锌联合使用时，表现出协同作用[55]。义齿清洁剂常搭配物理消毒法对义齿进行清洁，能较大程度减少消毒时间，还可提高整体的除菌效果，常见的有微波消毒、紫外线照射和超声震荡等方法，具有成本低、安全、速度快、易于操作的优点[48, 56-57]。除此之外，不同药物、药物与消毒方式之间联合使用均可提高抑菌效果。

近年来，有些义齿清洁剂通过加入植物配方，减少耐药菌株的产生，但仅限于目前研究较为深入的植物，如芦荟、绿茶等，后续可以将其他具有良好抗菌活性的植物纳入研究范围。

2.5. 材料改性

材料改性是指通过向义齿材料中添加杀菌剂的方法来修饰其树脂基体[58]。用抗菌剂进行义齿材料改性，赋予材料抗菌性能，弥补材料多孔结构的不足，成为防治DS的一条重要途径。常用的改性剂主要有金属纳米颗粒及天然提取物分子，其中金属纳米颗粒对义齿改性的研究最为深入。

2.5.1. 金属纳米分子

近年来纳米粒子(nanoparticles，NPs)被开发出多种实践用途。AgNPs改性义齿材料能抑制白色念珠菌生物膜的形成，但其抑菌性能具有浓度依赖性，且随着时间的延长而降低[59]。使用辣木叶提取物作为还原剂合成的AgNPs提高了对白色念珠菌的杀菌性，并且对正常细胞无害，值得在生物医学应用中进一步研究[60]。光沉积法合成的Ag/ZnONPs改性义齿材料在较低浓度也表现出优良的抗菌活性[61]。树脂材料掺入ZrO2NPs后具有明显且长期的抗白色念珠菌生物膜活性[62-63]。用MgONPs进行改性的聚乙烯醇/羧甲基纤维素对白色念珠菌具有很高的抗菌活性，可以作为义齿黏合剂的一种理想材料[64]。通过义齿基托分层技术制备TiO2NPs改性的聚甲基丙烯酸甲酯(polymethyl methacrylate，PMMA)可以有效减少白色念珠菌的黏附作用[65]。

金属纳米材料用于改性义齿基托材料是预防DS的一条途径。然而，在临床应用之前，还需进一步研究其安全性。

2.5.2. 天然提取物分子

近年来有研究[66-73]将天然提取物应用于义齿改性方面，在赋予义齿材料抗菌活性的同时，提高患者对义齿的安全感和满意度。

壳聚糖改性义齿材料对白色念珠菌表现出较强的体外抗菌活性，具有良好生物相容性，对义齿材料物理性能不产生影响，但抑制作用会随时间逐渐减弱[66]。负载于羟基磷灰石纳米管的百里香提取物涂层能赋予PMMA材料很好的抗白色念珠菌黏附和生长的特性[67]。PMMA上的肉桂纳米纤维涂层能减少白色念珠菌的黏附和增殖，且不影响上皮细胞的活力[68]。芦荟粉改性的义齿软衬材料不仅能抑制白色念珠菌的生长，还能提高改性材料的剪切黏连强度[69]。木贼、石榴精、蔓越橘和蕃樱桃提取物也可用于义齿材料改性以提高抗菌性能[70-71, 73]。

改性天然制剂用作义齿材料具有应用前景，但该方向的研究较少，未建立起一个系统的体系。在义齿改性中，要考虑改性分子和义齿材料的相容性，以及改良材料的药物释放动力学等因素。

3. 结 语

DS是一种多因素疾病，其发病机制涉及白色念珠菌、宿主免疫防御及义齿材料等多方面，严重危害义齿佩戴者的口腔健康。近年来，DS的防治策略在不断发展，抗真菌药物可有效抑制白色念珠菌的黏附与侵入，但长期使用或滥用易导致耐药菌株出现；天然抗真菌剂凭借其良好的抗真菌性和不易使病原菌产生耐药的特点广泛受到人们关注；激光治疗因其独特的抗真菌特性，也被认为是一种很有前景的治疗方式；义齿材料通过改性赋予义齿抗菌性，阻止病原菌的初始黏附也可以作为防治DS的长期策略。此外，药物搭配不同防治方法的联合使用对白色念珠菌展现出更好的抗菌性，但需要进一步研究并制定标准化和规范化治疗方案。DS的复杂性给新药的探索带来挑战，但随着新药物及新治疗方案研究的不断深入，将为预防和治疗DS带来新的思路。

基金资助

湖南省自然科学基金(2023JJ30815)；湖南省大学生创新训练项目(S20210031020072)；中南大学教育教学改革研究项目(2023JGB120)。

This work was supported by the Natural Science Foundation of Hunan Province (2023JJ30815), the College Student Innovation Training Program of Hunan Province (S20210031020072), and the Central South University Education and Teaching Reform Project (2023JGB120), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

杨凤徽 文献检索，论文撰写与修改；杨远超 论文撰写及修改；林孟纬、何欣仪 文献检索；阳燕 论文指导与修改。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023091411.pdf

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