郝珂楠 李新玲 何曉峰

綜述

臭氧治療在臨床醫(yī)療中的新進展

郝珂楠 李新玲 何曉峰

臭氧是由3個氧分子構(gòu)成的極不穩(wěn)定的氣體，其較氧氣易溶于水。臭氧應(yīng)用于醫(yī)學(xué)初始于20世紀(jì)初，最開始在一戰(zhàn)期間為傷員治療壞疽，戰(zhàn)爭結(jié)束后臭氧陸續(xù)被應(yīng)用于創(chuàng)面消毒、促進創(chuàng)面愈合、肝炎、關(guān)節(jié)炎及腰椎間盤突出癥等疾病的治療，并取得了較滿意的療效。臭氧治療作為一種非傳統(tǒng)的治療方式，因其安全、便捷、廉價等優(yōu)點正逐漸被人們接受[1]，極少有并發(fā)癥方面的報道。至今只有3例術(shù)后椎間盤感染的相關(guān)個案報道，其中1例為achromobacter xylosoxidans（一種機會性致病菌）[2]。但近期研究表明臭氧治療腰椎間盤突出癥術(shù)后出現(xiàn)骨關(guān)節(jié)粘連癥狀[3]，且自血療法可以導(dǎo)致人類急性冠脈綜合征[4]，這些并發(fā)癥還有待于我們進一步觀察。

腰椎間盤突出癥

腰背部疼痛為患者就診第5大原因，而90%成年人在生活中都出現(xiàn)過腰痛癥狀。該癥狀大多數(shù)與腰椎間盤突出有關(guān)[5]。椎間盤及周圍神經(jīng)根臭氧注射術(shù)已成為常用的治療椎間盤突出癥的手段，多數(shù)在DSA下進行，少量可在CT引導(dǎo)下進行[6-7]。其中椎間盤臭氧注射術(shù)為最常用的治療方式，其次為神經(jīng)根周圍注射臭氧[8]。椎間盤內(nèi)臭氧注射術(shù)可認為是一種可緩解患者疼痛癥狀較安全的治療方法[7,9-10]。

對于臭氧治療腰椎間盤突出癥的研究，近年也有一些新進展。研究證實，單純的臭氧注射術(shù)術(shù)后患者明顯出現(xiàn)疼痛緩解，并且緩解程度較內(nèi)科保守治療理想[11]；而單純的臭氧治療與臭氧+倍他米松聯(lián)合治療在術(shù)后疼痛癥狀緩解方面效果無明顯差別，提示我們臭氧在止痛方面有卓越表現(xiàn)[10,12]。有些研究并不拘泥于臭氧注射術(shù)本身，通過比較臭氧注射術(shù)及新興的Souchards全體姿態(tài)再教育(GPR)療效，證實臭氧消融術(shù)療效優(yōu)于GPR，并在遠期療效上取得優(yōu)勢[5]。對于腰椎間盤突出癥患者，臭氧不僅可減輕患者由神經(jīng)根受壓及炎癥刺激引起的疼痛，由神經(jīng)根癥狀導(dǎo)致的運動肌無力也有較好的治療及預(yù)防效果。經(jīng)過臭氧治療的患者，幾乎完全未出現(xiàn)運動肌無力癥狀[8]。有時，臭氧注射術(shù)聯(lián)合椎間盤射頻消融術(shù)的治療方式也常被臨床醫(yī)生采用。術(shù)后1個月聯(lián)合治療較單純射頻消融術(shù)并未顯現(xiàn)出明顯優(yōu)勢，但根據(jù)1年的隨訪結(jié)果可證實，聯(lián)合治療在緩解患者疼痛方面較單純的射頻消融術(shù)具有更好的療效[13]。MRI的T2相可作為椎間盤臭氧治療效果的評價手段[14]。

經(jīng)過多年的探索研究，臭氧治療腰椎間盤突出癥的主要機制有：臭氧可有效抑制局部炎癥反應(yīng)；緩解髓核缺氧癥狀；利用強氧化性破壞髓核內(nèi)的氨基多糖鏈，降低其含水量，導(dǎo)致縮小髓核體積(已被實驗中CT及MRI T2影像證實[6])，減輕壓迫癥狀；刺激成纖維細胞分裂增殖，起到修復(fù)作用[15]；恢復(fù)患者機體氧化應(yīng)激平衡[16]。

組織缺血再灌注

臭氧是一種強氧化氣體，早期實驗發(fā)現(xiàn)其可以激活體內(nèi)氧化還原系統(tǒng)，通過激活細胞外調(diào)節(jié)蛋白激酶和P38激酶，刺激Nrf2/EpRE（氧化應(yīng)激相關(guān)）的表達，促進了超氧化物歧化酶和過氧化氫酶的活性[17-19]。大鼠腎臟缺血再灌注實驗表明，臭氧自血療法不僅降低了腎臟缺血再灌注后血液中肌酐及尿素氮的濃度，還保護了腎臟組織結(jié)構(gòu)。這種保護作用與以往認為的調(diào)節(jié)NO通路無關(guān)，而是刺激了腎臟局部的βNADPH-硫辛酰胺脫氫酶濃度。在纖維電鏡下可以看到，臭氧促進了細胞內(nèi)部的氧化反應(yīng)及線粒體活動[20]。后續(xù)研究發(fā)現(xiàn)，臭氧調(diào)節(jié)了腎臟局部中性粒細胞聚集，IL-6、TNF-α及缺血修飾白蛋白的表達，提高了腎臟局部總抗氧能力[21]。

臭氧對于睪丸扭轉(zhuǎn)、卵巢扭轉(zhuǎn)造成的組織缺血再灌注及各種原因出現(xiàn)的腸缺血也有極佳的治療效果；土耳其科學(xué)家利用小鼠模型，證實了對于睪丸扭轉(zhuǎn)的小鼠，腹腔注射臭氧氣體或睪丸內(nèi)注射臭氧氣體對于睪丸扭轉(zhuǎn)術(shù)后的缺血再灌注均有較好的預(yù)防作用，且睪丸內(nèi)注射效果更佳[22]；腹腔注射臭氧氣體也對卵巢扭轉(zhuǎn)術(shù)后卵巢缺血再灌注損傷起到了預(yù)防、緩解的效果[23]。在腸系膜上動脈閉塞小鼠模型中，腹腔注射臭氧對腸道短時間缺血后再灌注造成的組織有保護作用，且超氧化物歧化酶活性較未接收治療組減少，降低組織損傷[24-25]；骨骼肌的缺血再灌注損傷中，臭氧治療通過降低肌肉內(nèi)的肌酸激酶、天冬氨酸轉(zhuǎn)氨酶和K+離子為組織提供了保護[26]。

再 生

研究證實臭氧可促進組織再生。對于二度燒傷患者，相較于最新的透明質(zhì)酸治療，臭氧油在促進創(chuàng)面愈合、抑制創(chuàng)面黑色素沉著方面有明顯優(yōu)勢，但在改善紅斑、緊張、瘙癢和燒灼感方面并無明顯差別[27]；一例由于骨筋膜室綜合癥導(dǎo)致的下肢骨骼及皮膚創(chuàng)面愈合困難的患者，經(jīng)過臭氧治療后得以治愈[28]。臨床腫瘤放射治療中，總會出現(xiàn)放療區(qū)域皮膚損傷或周圍軟組織損傷，臭氧的腹腔注射可預(yù)防及緩解這些損傷；如前列腺癌患者放療后的出血性腸炎，臭氧局部噴灑就顯著的緩解了腸道炎癥，減輕的患者的出血癥狀[29]。

基礎(chǔ)實驗方面，鼠皮瓣移植實驗證實了臭氧處理能提高移植皮瓣的成活率[30]。通過對放射性損傷、下肢靜脈曲張及麻風(fēng)引起的皮膚損傷的臨床臭氧應(yīng)用，證實了臭氧對于這些損傷具有預(yù)防及促進修復(fù)的功效[31-34]；對于門齒拔除的白鼠，臭氧腹腔注氣可以促進骨小梁形成，從而促進了骨質(zhì)再生[35]。亦有實驗證實，在先天顱骨缺陷的Wistar大鼠骨移植治療中加用臭氧治療，可以促進成骨細胞增殖，增加骨小梁數(shù)量，并促進了新骨生成[36]。而在以糖尿病小鼠為模型的實驗中，臭氧沖洗則促進受破壞股骨的血管再生及破骨細胞的遷移，但并未對骨小梁的形成產(chǎn)生任何影響[37]；臭氧可增加骨皮質(zhì)損傷股骨再生中的骨鈣素陽性細胞數(shù)，從而促進骨質(zhì)再生[38]。在部分切除肝臟的小鼠模型上，臭氧治療不僅保護了殘肝的肝功能，更抑制了組織IL-6的表達，減輕組織炎癥反應(yīng)，從而促進再生修復(fù)[39]。對于胰腺炎犬模型，臭氧治療可以加快壞死組織清除，減輕組織炎癥，從而促進胰腺修復(fù)，并可以將死亡率從60%降至20%[40]。在斑馬魚尾鰭再生的實驗中，我們證實了臭氧通過調(diào)節(jié)中性粒細胞的遷移及TNF-α、IL-1β的表達促進再生[41]。

口腔醫(yī)學(xué)

臭氧在口腔醫(yī)學(xué)中的應(yīng)用相當(dāng)廣泛，幾乎每天都在幫助口腔科醫(yī)生治療各種各樣的口腔疾病[42]。主要治療方式為：①臭氧漱口水[43]；②局部噴霧；③蛀牙及病變局部盥洗（還可以預(yù)防病變牙齒的臨近牙齒受到感染[44]）；④植牙之后減輕牙齦炎癥及出血風(fēng)險[45-46]；⑤牙齒漂白[47]；⑥預(yù)防和治療煙草依賴牙周炎[48]；⑦治療口腔扁平苔蘚[49]；⑧治療口腔潰瘍[50]。其治療機制可總結(jié)為以下方面：①強大的消毒能力(糞腸球菌，消毒能力與應(yīng)用頻次相關(guān))[51-56]，在口腔消毒中，臭氧氣體效果較洗必泰效果好[57]；②控制出血；③清洗骨骼和軟組織傷口；④通過增加局部組織氧氣的供應(yīng)促進傷口愈合；⑤臭氧水可以增加局部溫度,這與代謝過程與傷口愈合有關(guān)；⑥止痛[58]。

已知的臭氧治療口腔疾病的機制為：消炎鎮(zhèn)痛，增加局部供氧量，促進組織蛋白生成[59]。牙齦移植患者也可通過臭氧油的應(yīng)用促進傷口愈合[60]。但過高濃度的臭氧會通過降解牙齒中的膠原蛋白而對牙齒造成不可逆的損害[61]。與還原劑一起應(yīng)用時卻可以促進牙齒受損后的礦化修復(fù)[62]。對于齲齒修復(fù)術(shù)后患者，臭氧的各種治療并不會影響修補物的黏附性[63]。

糖尿病

臭氧對于糖尿病相關(guān)并發(fā)癥也有治療效果[64]。對于糖尿病的神經(jīng)損害，研究發(fā)現(xiàn)，糖尿病大鼠的神經(jīng)傳導(dǎo)速度、復(fù)合電位振幅及機體總抗氧化能力在接受胰島素或胰島素+臭氧治療后均有提高。即便是單獨應(yīng)用臭氧治療，復(fù)合電位振幅及機體總抗氧化能力也得到提升。而上述三種治療方案均降低了機體的總氧化狀態(tài)和氧化損傷程度。由此可以推斷臭氧作用于機體基本依靠調(diào)節(jié)氧化及抗氧化反應(yīng)[65]。臨床實驗證實，在糖尿病導(dǎo)致的患者足部潰瘍，臭氧水沖洗治療可促進傷口愈合，不論在愈合速度還是愈合率上均有較優(yōu)秀的表現(xiàn)[66-67]。對于糖尿病導(dǎo)致的肢體末端軟組織感染，臭氧自血療法+臭氧水創(chuàng)面沖洗，促進了組織細胞連接蛋白的分泌，如細胞連接蛋白-43（Cx43）和堿性纖維母細胞生長因子受體（β-FGFR），不論在愈合速度還是愈合率上均有較優(yōu)秀的表現(xiàn)[68-69]。而另外一個實驗則證實臭氧促進糖尿病患者下肢難愈性潰瘍愈合是因為促進了人體血管內(nèi)皮生長因子（VEGF）、轉(zhuǎn)化生長因子-β（TGF-β）及血小板源生長因子（PDGF）的表達[70]。糖尿病腎病鼠模型中，臭氧聯(lián)合胰島素治療可以有效的保護鼠的腎臟功能[71]，單獨的臭氧療法也可降低糖尿病大鼠腎組織中細胞凋亡基因Caspase-1-3-9、HIF-1α以及TNF-α的表達，并改善了腎組織結(jié)構(gòu)的改變，從而對腎臟功能起到了保護作用[72]。

其他系統(tǒng)疾病

臭氧治療除了可以用于治療感染的傷口,循環(huán)障礙以外，還對老年性黃斑變性、病毒性疾病、風(fēng)濕病、關(guān)節(jié)炎、癌癥、非典和艾滋病等疾病具有治療作用[73]。即便爭議頗多，但其臨床效果往往令人非常滿意。在無疾病人群中，臭氧自血療法就可以提高人體含氧血紅蛋白及細胞色素C的濃度，并可以刺激細胞色素C的活性[74]；增加乳糖及丙酮酸的含量，促進人體糖酵解過程，并增加了脂質(zhì)過氧化物及溶血磷脂在血液中的含量[75]。而在神經(jīng)系統(tǒng)疾病的患者，如多發(fā)性硬化癥，自血療法上述作用則更加明顯，從而對神經(jīng)系統(tǒng)疾病起到治療效果[74]。臭氧通過激活機體抗氧化系統(tǒng)，從而減緩了阿爾茨海默?。ˋD）的進展速度，該作用在男性患者的表現(xiàn)更加明顯[76]；即便最常見的由腦梗死引起的肢體癱瘓，臭氧自血療法在臨床療效及皮層電位上升率上較常規(guī)治療也表現(xiàn)出了優(yōu)勢[77]。對于頑固性頭痛患者，單次自血療法可以有效的緩解頭痛，效果可長達58個月[78]。然而對于耳鳴患者，同倍他司?。ㄖ饕糜谥委熋纺岚＞C合征、血管性頭痛及腦動脈硬化等）一樣，臭氧并未起到治療效果[79]。除神經(jīng)系統(tǒng)疾病外，老年性黃斑病在接受自血療法之后，其視力保持及恢復(fù)情況也較常規(guī)維生素治療好。該療效與臭氧降低患者反應(yīng)性氧代謝物并激活自身抗氧化反應(yīng)有關(guān)[80-81]。在高尿酸血癥及痛風(fēng)患者，醫(yī)生嘗試以自血療法進行治療。結(jié)果提示，不論是在肌酐清除率的下降還是痛風(fēng)患者疼痛緩解方面，自血療法均取得了較好的療效[82]。每天定時給予腹腔臭氧注射，可以通過降低血漿內(nèi)皮素-1、ET-受體A，增加腎素、一氧化氮及ET受體B的表達，從而降低實驗動物平均動脈血壓[83]；同時對于心率、腓腸肌和心肌肥厚和纖維化也有一定的影響；減少心臟和腓腸肌組織中乳酸脫氫酶、肌酸磷酸激酶、 肌鈣蛋白I，硝基酪氨酸的濃度[84]。對于腫瘤小鼠模型，臭氧腹腔注射治療也取得了與放療幾乎相同的治療效果[85]。對于膽道梗阻及甲氨喋呤導(dǎo)致的肝硬化，早期的臭氧干預(yù)亦可緩解甚至阻止肝硬化的發(fā)生[86-87]。

自20世紀(jì)20年代以來，臭氧治療在世界范圍逐漸得到廣泛應(yīng)用，但對于臭氧治療的系統(tǒng)研究時間尚短。雖然在各類疾病的臨床治療中，臭氧都表現(xiàn)出了卓越的療效，也得到了越來越多醫(yī)生的認可，但其具體的作用機制探討仍未深入，有待于我們繼續(xù)研究探索。

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2014-3-10）

（本文編輯： 翟仁友）

10.3877/cma.j.issn.2095-5782.2015.03.014

510515 廣州，南方醫(yī)科大學(xué)南方醫(yī)院介入診療科（郝珂楠、李新玲、何曉峰）

何曉峰，Email：ozonetherapy@126.com

郝珂楠,李新玲,何曉峰.臭氧治療在臨床醫(yī)療中的新進展[J/CD].中華介入放射學(xué)雜志:電子版,2015,3(3):168-172.