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光生物调节疗法治疗口腔黏膜病的相关机制

2024-01-26李儒李泽慧郑明和钟良军丁佩惠

激光生物学报 2023年5期
关键词:治疗

李儒 李泽慧 郑明和 钟良军 丁佩惠

收稿日期:2023-06-12;修回日期:2023-09-01。

基金项目:浙江省口腔疾病临床医学研究中心项目(2022-KFKT-08)。

作者简介:李儒,硕士研究生。

* 通信作者:李泽慧,副主任医师,主要从事口腔内科学方面的研究。E-mail: lizehui1123@126.com。

摘 要:光生物调节疗法作为口腔黏膜病治疗的辅助手段发展迅速,它通过细胞吸收光子能量,产生光化学效应,从而调节各种各样的生物过程来达到治疗目的。本文就减少炎症、加速组织愈合、缓解疼痛以及光生物调节的双向剂量作用4个方面进行综述,并深入探讨了其作用机制,以便为临床医师应用光生物调节疗法治疗口腔黏膜病提供更好的临床决策和依据。

关键词:光生物调节;治疗;口腔黏膜病;发色团;双相剂量反应

中图分类号:R781.5                         文献标志码:ADOI:10.3969/j.issn.1007-7146.2023.05.003

Mechanism of Photobiomodulation Therapy in the Treatment of Oral Mucosal Diseases

LI Ru1, 2, LI Zehui1, 2*, ZHENG Minghe1, 2, ZHONG Liangjun1, 2, DING Peihui3

(1. Stomatology Center, Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, China; 2. School of Stomatology, Hangzhou Normal University, Hangzhou 310015, China; 3. Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou 310000, China)

Abstract: Photobiomodulation (PBM) as an adjunct method for the treatment of oral mucosal diseases has developed rapidly. It is through the absorption of photon energy by cells, produce photochemical effects, and thus regulate a variety of biological processes to achieve therapeutic purposes. In this paper, the four aspects of reducing inflammation, accelerating tissue healing, relieving pain and bidirectional dose of PBM are reviewed, and the mechanism of their action is deeply discussed in order to provide clinicians with better clinical decision and basis for the treatment of oral mucosal diseases with PBM therapy.

Key words: photobiomodulation; treatment; oral mucosal disease; chromophore; biphasic dose response

(Acta Laser Biology Sinica, 2023, 32(5): 403-413)

口腔黏膜病是口腔某一部位黏膜的正常色澤、外形、完整性与功能等发生改变的一类疾病。其病变种类繁多,多数疾病病因不明,并可组合成复杂多样的口腔损害,包括感染、白色和红色病变、溃疡、水疱大疱性疾病等[1]。

口腔黏膜病的治疗以局部治疗为主,如口腔扁平苔藓(oral lichen planus,OLP)、复发性阿弗它溃疡(recurrent aphthous ulcer,RAU)等的标准治疗方案是局部应用类固醇和非甾体抗炎药,以及增强上皮再生的药物等[2-4]。传统治疗手段往往难以避开糖皮质激素类药物,这些药物在短期、适量使用的情况下是相对安全的,但是,如果患者免疫力低下或者长期、超量使用,则可能诱发新的口腔疾患,如各种类型的口腔念珠菌病(oral candidiasis)[5]。

光生物调节(photobiomodulation,PBM)疗法,又称低水平激光疗法(low level laser therapy,LLLT)[6]。它可以对不同细胞类型的细胞产生生物刺激作用,例如,增加细胞迁移和增殖,促进生长因子的表达,激活细胞的增殖等[7-10]。作为一种较新的治疗手段,PBM逐渐在口腔临床中开展应用,已成为多种口腔黏膜疾病的有效治疗方法,包括口腔感染性疾病(疱疹)、溃疡性疾病[11]、扁平苔藓[12]、黏膜下纤维性变[13]等。与传统方法相比,其具有很大优势,可以作为传统药物的替代品,且不涉及疼痛及副作用[14]。图1简单描述了PBM的细胞机制。

PBM的细胞和分子改变机制尚处于快速发展和有待进一步阐明的阶段。探寻PBM如何调节细胞增殖和迁移,以及与口腔黏膜愈合相关的生长因子和蛋白的表达,有助于评价疗效和支撑PBM在口腔黏膜病中的应用[11]。本综述旨在通过对过往文献进行汇总探究,期待能为广大临床医师及研究者提供工作指导和研究思路。

1 PBM与发色团

1.1 响应PBM的主要发色团

PBM的效应依赖于光对生物系统的影响。光生物学第一定律指出,光的光子必须被位于组织内的某些分子(称为发色团)吸收,才能产生生物学效应[16],随后下游细胞内的反应由光信号转导和放大驱动,介导细胞内ATP、ROS和一氧化氮(nitric oxide,NO)的浓度变化。

Passarella等[17]最先提出负责PBM有益作用的主要发色团位于线粒体内。光子通过激活线粒体和其他发色团中的细胞色素c氧化酶(cytochrome c oxidase,CCO)来刺激细胞内的化学变化。这些发色团充当光感受器,触发神经保护反应,改善新陳代谢,增加血液流动,促进神经再生,减少炎症和氧化应激[18]。

吸收NIR光谱范围内光的主要发色团是血红蛋白、肌红蛋白、黑色素和线粒体CCO[19],其中CCO最受关注。Karu等[20-21]首先提出PBM效应的作用谱与CCO的吸收谱相匹配,Wong-Riley等[22]证实了这一观察结果。CCO位于线粒体呼吸链的第四单元,是一种具有13个独立蛋白质亚单位的复杂分子,包含2个不同的铜中心CuA和CuB以及2个血红素中心(血红素a和血红素a3),每个金属中心以氧化或还原的状态存在,具有不同的吸收光谱。CCO可以很好地吸收NIR区(高达950 nm)的光[23],利用还原细胞色素c的电子将4个质子转移到分子氧,形成2个水分子,由此形成的质子梯度来驱动ATP合成酶的活性[16]。而ATP驱动许多生物化学过程,如蛋白质合成、信号通路激活等,即使是很小的增加也能提高生物利用度,为细胞代谢功能提供动力[1]。环磷酸腺苷(cyclic adenosine monophosphate,cAMP)和Ca2+是人体内2种主要的第二信使,ATP能激活cAMP,并与Ca2+泵活性有关,而Ca2+调节大多数人体生理活动,如肌肉收缩、血液凝固、神经信号传递、基因表达[24]。

1.2 响应PBM的其他发色团

负责PBM的其他发色团可能还包括:1)光门控离子通道和视蛋白。2)黄素和黄蛋白。与CCO和线粒体相比,视蛋白、光门控离子通道、黄素和隐蛋白(它们可能在多种细胞类型中广泛表达)支持PBM效应的证据仍不够充分,且它们很可能是对应蓝色和绿色光谱区域。3)超出CCO所吸收的波长之外观察到的光生物效应可能由水分子作为发色团负责,其机制涉及到结构水层(也称为界面水)[25]或水团[26]对红外光的选择性吸收,并可能影响蛋白质[27]构象、门控通道的打开、细胞内钙水平的调节[28]、ATP合酶的运转速度[29]等。需要进一步的研究来探索它们在抗炎、组织愈合和再生中的作用[30]。

2 PBM与炎症调控

炎症过程通常伴随着基因表达和信号传导的失衡,以及促炎细胞因子的释放,例如,肿瘤坏死因子-α(tumor necrosis factor,TNF-α)、ROS、氮类物质、白细胞介素-1β(interleukin-1β,IL-1β)和白细胞介素-6(interleukin-6,IL-6)[31]等。Bjordal等[32]的研究表明,PBM有类似于非甾体类抗炎药的作用;Fekrazad等[33]的研究表明,PBM可以减轻黏膜炎的严重程度。

2.1  PBM通过CCO影响NO

一个相对低能量的光子可以踢出结合在线粒体中并竞争性阻挡氧气的NO,允许呼吸过程快速发生[34],同时氧气消耗量增加并增加ATP的生成[35]。

Huang等[36]认为,CCO对光的吸收导致呼吸链电子转移速率的增加,从而增加ATP产生速率,并假设CCO具有2种酶活性:将NO2转化为NO和将O2还原为H2O。一方面,随着CCO活性的增加,NO的生成也增加[37](NO可以通过与O2竞争性地结合CCO而抑制呼吸,降低呼吸链中的电子转移率[36]);另一方面,PBM可能导致NO和CCO解离,从而为机体提供游离NO[36],这是一种由光增强的积极效果。最终的结论是:PBM促进了与CCO结合的NO产量的增加,并解离CCO和NO,更多的游离NO被释放出来。而游离NO可以增强下游效应,如全身血压、缺氧信号、应激反应途径、宿主微生物相互作用、免疫信号和凋亡等[1]。

2.2 ROS在PBM中的信号通路作用

ROS在体内稳态平衡和细胞信号传递中起着关键作用,在从线粒体到细胞核的细胞信号通路中发挥重要作用,可以调节细胞周期进程、蛋白质合成、核酸合成和相关酶激活[1]。研究表明,线粒体中吸收的红光/NIR光可产生适量的ROS[38]。

经典的观点认为,线粒体膜电位(mitochondrial transmembrane potential,MMP)的增加会导致ROS增加[39],而PBM能增加MMP。炎症和代谢性疾病,与线粒体ROS产生紊乱有关[40]。功能失调的线粒体会产生更多ROS,这个过程的特点是一个被称为“ROS诱导的ROS释放(ROS-induced ROS release,RIRR)”的自放大反馈回路[41]。细胞在暴露于过度或长期氧化应激等条件下,ROS的增加可能达到阈值水平,从而触发线粒体通道的开放,如线粒体通透性转换孔或线粒体内膜阴离子通道,这些通道的激活反过来导致MMP增加,并通过呼吸链增加ROS生成[42]。当足够多的ROS产生后,其可能会作为“第二信使”激活邻近线粒体中的RIRR,从而充当另一个破坏性反馈回路,增加细胞损伤[43]。

当PBM刺激正常健康细胞的CCO活性时,其MMP会高于正常基线水平,导致ROS的生成短暂而适度的增加[44],ROS产量短暂增加后,因抗炎标志物的释放、炎症介质和中性粒细胞浸润减少,炎症会减轻[1];当PBM被应用到已经受到氧化应激损伤的细胞时,PBM能使其MMP和ATP恢复至基线附近,减少ROS的生成[16]。最新的研究表明:NIR光与CCO相互作用,瞬时减弱CCO活性,减弱线粒体膜电位超极化,从而减少ROS的产生;而高水平的ROS可以促进环氧化酶-2(cyclooxygenase-2,COX-2)的表达,从而促进细胞产生更多的前列腺素E2(prostaglandin-E2,PG-E2)和白细胞介素-8(interleukin-8,IL-8)[45-46]。而口腔黏膜炎症主要是由过量ROS的形成和NF-κB的激活引起的[1],因此,PBM可以通过抑制细胞内ROS的水平来抑制炎症[47]。

NF-κB是一种转录因子,其通路是细胞内氧化应激后激活的主要信号通路[48],可调节多种炎症细胞因子,包括TNF-α、白细胞介素-1(interleukin-1,IL-1)、IL-6和IL-8[49]。Chen等[44]认为,细胞中NF-κB的激活与ROS水平有关,ROS水平的增高会激活NF-κB,即PBM可以通过减少过多的ROS来对抗NF-κB的激活。

3 PBM与组织修复

PBM激活各种细胞因子,促进免疫细胞迁移到感染部位[50],产生适应性免疫来对抗伤口愈合过程中存在的病原体[1],调节细胞(促进增殖和细胞迁移),促进抗凋亡蛋白和胶原等的合成,从而加速伤口愈合,减少疼痛、肿胀和炎症[44]。

3.1 PBM调节各种细胞因子

口腔黏膜炎症会激活T细胞和招募巨噬细胞,从而导致促炎细胞因子和转化生长因子-β(transforming growth factor-β,TGF-β)水平升高。TGF-β可以通过激活前胶原蛋白基因、上调前胶原蛋白酶以及赖氨基氧化酶的活性来显著增加胶原蛋白含量[51]。

有2种细胞因子在伤口愈合中起着重要作用[1]。IL-6在损伤反应中起着核心作用,它是一种具有功能多效性的细胞因子,在宿主防御中起重要作用。当感染或组织损伤发生时,单核细胞和巨噬细胞迅速产生IL-6,并通过激活免疫、血液和急性期反应,帮助清除感染因子和修复受损组织。一旦应激消失,IL-6的合成就会终止,但不受控制的过量或持续的IL-6产生在各种炎症性疾病中起着负面作用[52]。白细胞介素-10(interleukin-10,IL-10)是一种抗炎细胞因子,可以抑制促炎细胞因子的产生以及巨噬细胞和中性粒细胞的浸润[53],调节Th1/Th2平衡(Th1免疫反应是促炎反应,Th2免疫反应是抗炎反应)并抑制T淋巴细胞增殖[54]。

在OLP患者中,体内会产生高水平的IL-6并加剧局部炎症反应和不适[55]。血清和唾液中的高水平IL-10可能与防御反应有关,防止免疫細胞造成过多的组织损伤[56-57]。在炎症性疾病的试验模型中,PBM能够降低过量IL-6的水平,从而有助于炎症消退并促进组织修复[30-58]。在合适的辐射能量下,PBM能显著降低大鼠口内溃疡组织中促炎性IL-6的表达,还能提高TGF-β和基质金属蛋白酶-2(matrix metalloproteinase-2,MMP-2)的表达[59]。

在口腔黏膜下纤维化等疾病中,活化的炎性细胞产生细胞因子(如IL-6)并促进生成纤维化的生长因子,导致胶原合成增加,胶原降解减少[13]。PBM可以降低颊黏膜下病变中纤维化标志基因α-平滑肌肌动蛋白和结缔组织生长因子的蛋白表达[60],还能在体外通过cAMP信号抑制槟榔碱介导的纤维化标记基因的表达[61],抑制成纤维细胞-肌成纤维细胞转变[62]。

PBM可以增加血管内皮生长因子(vascular endothelial growth factor,VEGF)的生成,帮助血管生成、改善微循环,诱导中性粒细胞浸润和减少COX-2表达,从而促进伤口愈合[63]。生长因子如碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)有助于调节成纤维细胞增殖和迁移,转化生长因子-α(transforming growth factor-α,TGF-α)可诱导成纤维细胞合成胶原,而PBM可以激活这些因子的产生[1]。Gupta等[64]通过大鼠试验证明,PBM组大鼠创面愈合更快,其TNF-α和NF-κB表达减少,炎症减少,VEGF及成纤维细胞生长因子-1(fibroblast growth factor-1,FGF-1)等表达上调。

3.2 成纤维细胞主导的增殖修复作用

成纤维细胞的激活在PBM诱导的组织修复中起着主要作用,其增殖、分化和迁移以及最终刺激上皮细胞的生物活性被认为是口腔黏膜愈合过程中的关键因素[65]。PBM能增强成纤维细胞的增殖、成熟和运动能力,并增加bFGF的产生[66-67],在合适的波长和剂量方案下,其能诱导成纤维细胞增殖和增加胶原蛋白的合成[1]。

大多数体外试验结果显示,PBM处理后成纤维细胞增殖增加,包括大鼠成纤维细胞[68]、大鼠肌成纤维细胞[67]、小鼠胚胎成纤维细胞[69]、鸡胚成纤维细胞[70]、人成纤维细胞[69]、人牙龈成纤维细胞[71-72]等,其增殖均不同程度增加。

成纤维细胞能和角质形成细胞相互串扰,促进角质形成细胞的迁移和增殖[73]。此外,淋巴细胞被PBM激活并更快地增殖,巨噬细胞作为吞噬细胞的能力也得到增强[15],从而促进组织修复。

3.3 PBM的长期修复效应

许多次级介质(ROS、NO、cAMP)能够激活转录因子和信号通路,转录因子的激活可以解释为什么相对短暂的光照可以产生持久的效果[16]。PBM促进氧代谢产生的ROS可以激活转录因子,促使各种刺激和保护基因的上调[15]。当ROS数量增加时,细胞发出信号招募抗氧化分子。这些信号通路的激活上调了转录因子的基因表达[1]。此外,NO也可以刺激血管扩张,并间接调节许多基因的转录[37]。

另外,干细胞数量及活性的增加也能说明PBM短期治疗可以产生长期效益,PBM对干细胞有正向作用,其可以增强干细胞的生物活性,例如,细胞迁移、增殖、存活和整体细胞生态位[74-75]。PBM还能显著增加干细胞的初始数量[76],并增强干细胞分化[77]。在一项临床研究中发现,PBM可能通过抗氧化、促进再生等机制,在相当长的时期内缓解口腔疼痛不适[如灼口综合征(burning mouth syndrome,BMS)、口腔医源性神经病变],还证明了PBM具有持久的、神经再生的有益作用[78]。另一项研究也表明,PBM治疗后,OLP的症状改善且其疗效至少持续了3个月[79]。

4 PBM与疼痛缓解

PBM对疼痛总体有积极的治疗效果[80],可以降低疼痛评分[81]。其缓解疼痛的机制可能是通过对神经元及疼痛介质的调节,影响炎症因子的生成,促进局部血液循环及组织愈合再生等,有效减轻即时疼痛和远期疼痛。

4.1 PBM对神经的调节

光子能够穿透表层神经元来调节疼痛[82]。首先,PBM通过其对Na+/K+泵的作用改变病损周围神经元的神经传导和兴奋性[83]。此外,其还可以对瞬时受体电位阳离子通道亚家族成员1和神经生长因子信号阻滞剂造成影响,减少它们的表达(阻断炎性热痛觉),从而有效减少有害刺激[84]。通过引起膜通透性的可逆变化,PBM进一步刺激细胞活性和增殖,同时降低C和Aδ神经纤维活性[15-85],抑制传入疼痛纤维[86]。NIR和红外波长还可降低躯体感觉电位的幅度,减少脊髓神经元中的P物质,从而产生镇痛作用[87]。

4.2 PBM与阿片肽

PBM在β-内啡肽和脑啡肽的产生以及降低缓激肽和组胺水平方面起着关键作用,有助于镇痛和缓解疼痛[88-89],减弱P物质释放以及缓激肽、组胺和PG-E2的分泌,并抑制传入疼痛纤维[86]。1993年,Honmura等[90]研究发现,半导体激光照射能消除炎症性痛觉,且其镇痛作用至少部分是由内源性阿片释放引起的(G蛋白偶联受体家族的成员[91]之一阿片受体,被激活后可产生强烈的止痛效果),并可通过免疫系统细胞的迁移增加外周内源性阿片类物质的释放。此外,PBM还可通过激活外周阿片受体,来减少痛觉[92]。

4.3 PBM与炎性介质

促炎细胞因子,如TNF-α、IL-6、白细胞介素-12(interleukin-12,IL-12)、IL-1β、ROS是放大炎症反应和使初级伤害性神经元敏感化的炎症介质[93-94],而白细胞介素-4(interleukin-4,IL-4)、IL-10和白细胞介素-13(interleukin-13,IL-13)是重要的抗炎细胞因子,限制炎症反应。在动物模型中,PBM可显著减少TNF-α和IL-1β的生成[95],增加组织IL-10的水平[92]。PG-E2是环氧化酶的产物,是已知的对炎性疼痛和痛觉过敏有显著影响的脂质介质[96]。PBM可以下调PG-E2水平[97-98],其通过下调COX-2,从而下调PG-E2,减少痛敏效应和炎症反应[82],减轻由前列腺素等细胞内信号分子介导的炎症相关疼痛[99]。此外,PBM还可以减少水肿和炎性细胞迁移[100]。

ROS和疼痛也有关联,异常的ROS引起的氧化应激可导致慢性炎症[101]。因此,过氧化氢酶和超氧化物歧化酶活性的增加也可能是PBM治疗炎性疼痛的有效机制之一[92]。NO在疼痛中也起作用[102]。许多动物研究表明,抑制NO合成可以显著减轻炎症性和神经病理性疼痛[103-106],而PBM能以剂量依赖的方式降低NO的产生。

4.4 PBM的长期止痛效果

伤口愈合和组织再生可能是PBM治疗疼痛的长期效果的主要作用方面。在细胞增殖和凋亡抑制中发挥作用的基因受PBM的调节[107]。有证据表明,PBM可以促进内皮细胞[108]、成纤维细胞[109-110]和角质形成细胞[111]的增殖,还可以促进胶原合成、刺激血管生成、增加血流量[112-113],并促进神经再生[114-115]。如在对BMS的治疗中,其能影响微循环,刺激血管生成蛋白的分泌,进而影响微血管模式,减少因炎症导致的血管扩张,并减轻烧灼感[116]。

5 PBM的双相作用

PBM对机体的益处,包括减少炎症因子、抗炎、促进血液循环、促进细胞活化与增殖等。由于PBM的双相剂量效应以及不同细胞对PBM的反应也有所不同,它的效用也并不总是有益的。但总的来讲,绝大多数情况下,PBM益处远远大于其副作用。

5.1 双相剂量效应

PBM具有双相剂量效应的特点。双相剂量效应是指:如果所施加的光没有足够的辐照度或照射时间太短,则没有反应;如果辐照度太高或照射时间太长,则响应可能被抑制[117-119]。即PBM的“剂量”有一个最优值,通常用能量密度(J/cm2)来定义[120-121]。当PBM的剂量增加时,在某个值就会达到最大反应,如果剂量增加到超过这个最大值,反应就会减弱甚至消失,而在非常高的剂量下还會产生负面或抑制作用[30]。Courtois等[1]的结论是:为了使生物过程发生,细胞必须接受一个双相剂量,低水平激光在刺激和修复组织方面比高水平的光有更好的效果。如在体外创面愈合模型中,使用650 nm波长、10 J/cm2的高剂量辐照,细胞迁移和增殖均出现了减少现象[122]。既往研究表明,具有更明显临床效果的参数在1~10 J/cm2的能量密度范围内[14],如在RAU中,指南建议每次使用应低于10 J/cm2[123]。Albrektson等[124]和Jijin等[125]分别使用6.3 J/cm2 和6 J/cm2 能量密度的激光,即有效改善RAU的症状;Cafaro[126]等的研究表明,980 nm、4 J/cm2的PBM即可有效减轻OLP疼痛并减少损伤;在一项随机对照试验研究中,以4.5 J/cm2或3 J/cm2治疗复发性唇疱疹,取得了很好的疗效[127]。

5.2  细胞的保护作用

PBM能保护细胞(通常是神经元细胞)免受有毒物质的攻击,并能保护因毒素治疗(如化疗药物)而有死亡风险的细胞[1]。例如,电压依赖性钠通道阻滞剂(如河豚毒素)通过阻止神经元冲动、减少ATP需求和下调CCO活性发挥毒性,而使用670 nm LED的PBM处理可以将CCO活性恢复到正常水平或甚至更高[128]。

5.3 PBM的促癌作用

大部分研究表明,PBM对癌细胞没有负面影响,高剂量、低功率激光照射可以通过光灭活呼吸链氧化酶诱导癌细胞凋亡和抗肿瘤免疫反应[129]。高照射剂量PBM还可以对恶性细胞产生抑制作用[130-132]。

少部分研究发现,PBM可造成生物刺激,促进恶性细胞增殖[1],并激活一系列参与肿瘤传导的通路和介质[133]。Sperandio等[134]认为,PBM可以显著影响与口腔癌进展和侵袭相关的蛋白的表达,并可能加快口腔癌的恶性病程。Henriques等[135]认为,PBM可以影响细胞周期蛋白D1、β-连环蛋白、E-钙黏蛋白和基质金属蛋白酶-9的表达,促进人舌鳞状细胞癌细胞系细胞的增殖和侵襲。

因此,在靠近已知或可能存在肿瘤的区域时,应谨慎考虑使用PBM[136],因为有较低的利于恶性细胞的增殖、促进恶性病变的发展的可能。

5.4 PBM诱导的细胞毒性及DNA损伤

PBM后的细胞可因产生ROS和NO而导致细胞毒性,即使在低浓度的情况下,ROS也可以通过脂质过氧化、DNA链断裂和蛋白质破碎来破坏细胞成分[44]。

在PBM直接导致的健康细胞损伤方面,目前的文献证据尚不充足。在DNA损伤方面,Khan等[137]的观点是NIR激光可能不具有基因毒性或诱变性;Kujawa等[138]认为只有在高(15.0 J/cm2)的辐射照射下才观察到具有统计学意义的DNA损伤;另有研究表明,使用10 J/cm2和16 J/cm2的辐射照度可以损害细胞膜和DNA,使细胞活力和细胞增殖降低[139]。

5.5 PBM在炎症中的双向作用

一篇最新的回顾研究总结了PBM在抗炎试验中的双相作用,发现细胞或组织的炎症反应符合双相剂量效应:低剂量比高剂量更能抑制炎症,低剂量可以降低TNF-α、IL-1β和IL-6等促炎因子的水平,增加抗炎因子如IL-10的水平,提高细胞存活率,抑制活性氧的生成,抑制M1巨噬细胞中炎症因子的表达、下调转录因子NF-κB p65的表达和磷酸化来限制炎症;而高输出能量的PBM可能减少了炎症细胞迁移,且对炎症介质(如IL-1β和IL-6)的调节作用弱于低剂量[140]。

6 总结与展望

口腔黏膜病常常给患者造成巨大痛苦,对患者的饮食、睡眠、工作等造成不良影响。目前局部治疗的主流方案是局部用药,但应用局部药物易被口内外环境影响,且长期使用也有可能对全身造成不良影响。

随着相应机理的阐明,PBM也逐渐应用到口腔领域。很多学者将其与传统治疗方法比较,展示了PBM疗法应用在口腔疾病治疗中的巨大优势和潜力。目前,PBM的功效可能仍然是首先依靠发色团来引发,以线粒体为枢纽,并介导后续的各种信号通路及生化反应,产生一定的即时效应和远期效应。此外,PBM治疗口腔黏膜疾病功效的显现并非通过单一因素的影响,如PBM减轻OLP病变的体征和症状是通过促进成纤维细胞增殖、分化和迁移、刺激上皮细胞的生物活性,调节口腔组织中细胞因子和免疫细胞的释放,促进微循环,调节神经传递和神经再生等来控制口腔黏膜病损,恢复黏膜的健康代谢功能。

然而,目前支撑PBM治疗口腔黏膜病的相关分子机制以及PBM局部应用与全身关系方面的论述并不完善,这可能是由于PBM在细胞内引发反应产生的相关物质难以检测的原因。有关PBM的研究数据大多是在体外或通过动物试验得到的,考虑到其极低的副作用,未来的发展趋势可能会将研究重心从动物试验转移到临床试验中去,或与临床试验相结合,而不是单纯对比临床治疗效果得出重复的“PBM治疗某种疾病有效”或“与传统方法相比PBM更优”的结论。同时,由于PBM的基本生化机制尚不完全明确,部分研究结果存在争议,其使用难以标准化。未来的研究可继续探索PBM的生理生化机制、更准确的剂量参数等,并与其他已经建立的临床疗法结合起来转化为新的治疗方法指导PBM的临床应用。

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