郝珂楠 李新玲 何晓峰

综述

臭氧治疗在临床医疗中的新进展

郝珂楠 李新玲 何晓峰

臭氧是由3个氧分子构成的极不稳定的气体，其较氧气易溶于水。臭氧应用于医学初始于20世纪初，最开始在一战期间为伤员治疗坏疽，战争结束后臭氧陆续被应用于创面消毒、促进创面愈合、肝炎、关节炎及腰椎间盘突出症等疾病的治疗，并取得了较满意的疗效。臭氧治疗作为一种非传统的治疗方式，因其安全、便捷、廉价等优点正逐渐被人们接受[1]，极少有并发症方面的报道。至今只有3例术后椎间盘感染的相关个案报道，其中1例为achromobacter xylosoxidans（一种机会性致病菌）[2]。但近期研究表明臭氧治疗腰椎间盘突出症术后出现骨关节粘连症状[3]，且自血疗法可以导致人类急性冠脉综合征[4]，这些并发症还有待于我们进一步观察。

腰椎间盘突出症

腰背部疼痛为患者就诊第5大原因，而90%成年人在生活中都出现过腰痛症状。该症状大多数与腰椎间盘突出有关[5]。椎间盘及周围神经根臭氧注射术已成为常用的治疗椎间盘突出症的手段，多数在DSA下进行，少量可在CT引导下进行[6-7]。其中椎间盘臭氧注射术为最常用的治疗方式，其次为神经根周围注射臭氧[8]。椎间盘内臭氧注射术可认为是一种可缓解患者疼痛症状较安全的治疗方法[7,9-10]。

对于臭氧治疗腰椎间盘突出症的研究，近年也有一些新进展。研究证实，单纯的臭氧注射术术后患者明显出现疼痛缓解，并且缓解程度较内科保守治疗理想[11]；而单纯的臭氧治疗与臭氧+倍他米松联合治疗在术后疼痛症状缓解方面效果无明显差别，提示我们臭氧在止痛方面有卓越表现[10,12]。有些研究并不拘泥于臭氧注射术本身，通过比较臭氧注射术及新兴的Souchards全体姿态再教育(GPR)疗效，证实臭氧消融术疗效优于GPR，并在远期疗效上取得优势[5]。对于腰椎间盘突出症患者，臭氧不仅可减轻患者由神经根受压及炎症刺激引起的疼痛，由神经根症状导致的运动肌无力也有较好的治疗及预防效果。经过臭氧治疗的患者，几乎完全未出现运动肌无力症状[8]。有时，臭氧注射术联合椎间盘射频消融术的治疗方式也常被临床医生采用。术后1个月联合治疗较单纯射频消融术并未显现出明显优势，但根据1年的随访结果可证实，联合治疗在缓解患者疼痛方面较单纯的射频消融术具有更好的疗效[13]。MRI的T2相可作为椎间盘臭氧治疗效果的评价手段[14]。

经过多年的探索研究，臭氧治疗腰椎间盘突出症的主要机制有：臭氧可有效抑制局部炎症反应；缓解髓核缺氧症状；利用强氧化性破坏髓核内的氨基多糖链，降低其含水量，导致缩小髓核体积(已被实验中CT及MRI T2影像证实[6])，减轻压迫症状；刺激成纤维细胞分裂增殖，起到修复作用[15]；恢复患者机体氧化应激平衡[16]。

组织缺血再灌注

臭氧是一种强氧化气体，早期实验发现其可以激活体内氧化还原系统，通过激活细胞外调节蛋白激酶和P38激酶，刺激Nrf2/EpRE（氧化应激相关）的表达，促进了超氧化物歧化酶和过氧化氢酶的活性[17-19]。大鼠肾脏缺血再灌注实验表明，臭氧自血疗法不仅降低了肾脏缺血再灌注后血液中肌酐及尿素氮的浓度，还保护了肾脏组织结构。这种保护作用与以往认为的调节NO通路无关，而是刺激了肾脏局部的βNADPH-硫辛酰胺脱氢酶浓度。在纤维电镜下可以看到，臭氧促进了细胞内部的氧化反应及线粒体活动[20]。后续研究发现，臭氧调节了肾脏局部中性粒细胞聚集，IL-6、TNF-α及缺血修饰白蛋白的表达，提高了肾脏局部总抗氧能力[21]。

臭氧对于睾丸扭转、卵巢扭转造成的组织缺血再灌注及各种原因出现的肠缺血也有极佳的治疗效果；土耳其科学家利用小鼠模型，证实了对于睾丸扭转的小鼠，腹腔注射臭氧气体或睾丸内注射臭氧气体对于睾丸扭转术后的缺血再灌注均有较好的预防作用，且睾丸内注射效果更佳[22]；腹腔注射臭氧气体也对卵巢扭转术后卵巢缺血再灌注损伤起到了预防、缓解的效果[23]。在肠系膜上动脉闭塞小鼠模型中，腹腔注射臭氧对肠道短时间缺血后再灌注造成的组织有保护作用，且超氧化物歧化酶活性较未接收治疗组减少，降低组织损伤[24-25]；骨骼肌的缺血再灌注损伤中，臭氧治疗通过降低肌肉内的肌酸激酶、天冬氨酸转氨酶和K+离子为组织提供了保护[26]。

再 生

研究证实臭氧可促进组织再生。对于二度烧伤患者，相较于最新的透明质酸治疗，臭氧油在促进创面愈合、抑制创面黑色素沉着方面有明显优势，但在改善红斑、紧张、瘙痒和烧灼感方面并无明显差别[27]；一例由于骨筋膜室综合症导致的下肢骨骼及皮肤创面愈合困难的患者，经过臭氧治疗后得以治愈[28]。临床肿瘤放射治疗中，总会出现放疗区域皮肤损伤或周围软组织损伤，臭氧的腹腔注射可预防及缓解这些损伤；如前列腺癌患者放疗后的出血性肠炎，臭氧局部喷洒就显著的缓解了肠道炎症，减轻的患者的出血症状[29]。

基础实验方面，鼠皮瓣移植实验证实了臭氧处理能提高移植皮瓣的成活率[30]。通过对放射性损伤、下肢静脉曲张及麻风引起的皮肤损伤的临床臭氧应用，证实了臭氧对于这些损伤具有预防及促进修复的功效[31-34]；对于门齿拔除的白鼠，臭氧腹腔注气可以促进骨小梁形成，从而促进了骨质再生[35]。亦有实验证实，在先天颅骨缺陷的Wistar大鼠骨移植治疗中加用臭氧治疗，可以促进成骨细胞增殖，增加骨小梁数量，并促进了新骨生成[36]。而在以糖尿病小鼠为模型的实验中，臭氧冲洗则促进受破坏股骨的血管再生及破骨细胞的迁移，但并未对骨小梁的形成产生任何影响[37]；臭氧可增加骨皮质损伤股骨再生中的骨钙素阳性细胞数，从而促进骨质再生[38]。在部分切除肝脏的小鼠模型上，臭氧治疗不仅保护了残肝的肝功能，更抑制了组织IL-6的表达，减轻组织炎症反应，从而促进再生修复[39]。对于胰腺炎犬模型，臭氧治疗可以加快坏死组织清除，减轻组织炎症，从而促进胰腺修复，并可以将死亡率从60%降至20%[40]。在斑马鱼尾鳍再生的实验中，我们证实了臭氧通过调节中性粒细胞的迁移及TNF-α、IL-1β的表达促进再生[41]。

口腔医学

臭氧在口腔医学中的应用相当广泛，几乎每天都在帮助口腔科医生治疗各种各样的口腔疾病[42]。主要治疗方式为：①臭氧漱口水[43]；②局部喷雾；③蛀牙及病变局部盥洗（还可以预防病变牙齿的临近牙齿受到感染[44]）；④植牙之后减轻牙龈炎症及出血风险[45-46]；⑤牙齿漂白[47]；⑥预防和治疗烟草依赖牙周炎[48]；⑦治疗口腔扁平苔藓[49]；⑧治疗口腔溃疡[50]。其治疗机制可总结为以下方面：①强大的消毒能力(粪肠球菌，消毒能力与应用频次相关)[51-56]，在口腔消毒中，臭氧气体效果较洗必泰效果好[57]；②控制出血；③清洗骨骼和软组织伤口；④通过增加局部组织氧气的供应促进伤口愈合；⑤臭氧水可以增加局部温度,这与代谢过程与伤口愈合有关；⑥止痛[58]。

已知的臭氧治疗口腔疾病的机制为：消炎镇痛，增加局部供氧量，促进组织蛋白生成[59]。牙龈移植患者也可通过臭氧油的应用促进伤口愈合[60]。但过高浓度的臭氧会通过降解牙齿中的胶原蛋白而对牙齿造成不可逆的损害[61]。与还原剂一起应用时却可以促进牙齿受损后的矿化修复[62]。对于龋齿修复术后患者，臭氧的各种治疗并不会影响修补物的黏附性[63]。

糖尿病

臭氧对于糖尿病相关并发症也有治疗效果[64]。对于糖尿病的神经损害，研究发现，糖尿病大鼠的神经传导速度、复合电位振幅及机体总抗氧化能力在接受胰岛素或胰岛素+臭氧治疗后均有提高。即便是单独应用臭氧治疗，复合电位振幅及机体总抗氧化能力也得到提升。而上述三种治疗方案均降低了机体的总氧化状态和氧化损伤程度。由此可以推断臭氧作用于机体基本依靠调节氧化及抗氧化反应[65]。临床实验证实，在糖尿病导致的患者足部溃疡，臭氧水冲洗治疗可促进伤口愈合，不论在愈合速度还是愈合率上均有较优秀的表现[66-67]。对于糖尿病导致的肢体末端软组织感染，臭氧自血疗法+臭氧水创面冲洗，促进了组织细胞连接蛋白的分泌，如细胞连接蛋白-43（Cx43）和碱性纤维母细胞生长因子受体（β-FGFR），不论在愈合速度还是愈合率上均有较优秀的表现[68-69]。而另外一个实验则证实臭氧促进糖尿病患者下肢难愈性溃疡愈合是因为促进了人体血管内皮生长因子（VEGF）、转化生长因子-β（TGF-β）及血小板源生长因子（PDGF）的表达[70]。糖尿病肾病鼠模型中，臭氧联合胰岛素治疗可以有效的保护鼠的肾脏功能[71]，单独的臭氧疗法也可降低糖尿病大鼠肾组织中细胞凋亡基因Caspase-1-3-9、HIF-1α以及TNF-α的表达，并改善了肾组织结构的改变，从而对肾脏功能起到了保护作用[72]。

其他系统疾病

臭氧治疗除了可以用于治疗感染的伤口,循环障碍以外，还对老年性黄斑变性、病毒性疾病、风湿病、关节炎、癌症、非典和艾滋病等疾病具有治疗作用[73]。即便争议颇多，但其临床效果往往令人非常满意。在无疾病人群中，臭氧自血疗法就可以提高人体含氧血红蛋白及细胞色素C的浓度，并可以刺激细胞色素C的活性[74]；增加乳糖及丙酮酸的含量，促进人体糖酵解过程，并增加了脂质过氧化物及溶血磷脂在血液中的含量[75]。而在神经系统疾病的患者，如多发性硬化症，自血疗法上述作用则更加明显，从而对神经系统疾病起到治疗效果[74]。臭氧通过激活机体抗氧化系统，从而减缓了阿尔茨海默病（AD）的进展速度，该作用在男性患者的表现更加明显[76]；即便最常见的由脑梗死引起的肢体瘫痪，臭氧自血疗法在临床疗效及皮层电位上升率上较常规治疗也表现出了优势[77]。对于顽固性头痛患者，单次自血疗法可以有效的缓解头痛，效果可长达58个月[78]。然而对于耳鸣患者，同倍他司汀（主要用于治疗梅尼埃综合征、血管性头痛及脑动脉硬化等）一样，臭氧并未起到治疗效果[79]。除神经系统疾病外，老年性黄斑病在接受自血疗法之后，其视力保持及恢复情况也较常规维生素治疗好。该疗效与臭氧降低患者反应性氧代谢物并激活自身抗氧化反应有关[80-81]。在高尿酸血症及痛风患者，医生尝试以自血疗法进行治疗。结果提示，不论是在肌酐清除率的下降还是痛风患者疼痛缓解方面，自血疗法均取得了较好的疗效[82]。每天定时给予腹腔臭氧注射，可以通过降低血浆内皮素-1、ET-受体A，增加肾素、一氧化氮及ET受体B的表达，从而降低实验动物平均动脉血压[83]；同时对于心率、腓肠肌和心肌肥厚和纤维化也有一定的影响；减少心脏和腓肠肌组织中乳酸脱氢酶、肌酸磷酸激酶、 肌钙蛋白I，硝基酪氨酸的浓度[84]。对于肿瘤小鼠模型，臭氧腹腔注射治疗也取得了与放疗几乎相同的治疗效果[85]。对于胆道梗阻及甲氨喋呤导致的肝硬化，早期的臭氧干预亦可缓解甚至阻止肝硬化的发生[86-87]。

自20世纪20年代以来，臭氧治疗在世界范围逐渐得到广泛应用，但对于臭氧治疗的系统研究时间尚短。虽然在各类疾病的临床治疗中，臭氧都表现出了卓越的疗效，也得到了越来越多医生的认可，但其具体的作用机制探讨仍未深入，有待于我们继续研究探索。

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2014-3-10）

（本文编辑： 翟仁友）

10.3877/cma.j.issn.2095-5782.2015.03.014

510515 广州，南方医科大学南方医院介入诊疗科（郝珂楠、李新玲、何晓峰）

何晓峰，Email：ozonetherapy@126.com

郝珂楠,李新玲,何晓峰.臭氧治疗在临床医疗中的新进展[J/CD].中华介入放射学杂志:电子版,2015,3(3):168-172.