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上皮粘膜在放化療作用下發(fā)生炎癥反應(yīng)可導(dǎo)致粘膜炎，粘膜炎可影響胃腸道和口腔，導(dǎo)致患者疼痛、無(wú)法進(jìn)食、體重減輕甚至造成局部感染。此外，級(jí)別嚴(yán)重的粘膜炎可導(dǎo)致患者化療劑量降低或抗腫瘤治療延遲，最終影響患者的抗腫瘤療效和預(yù)后。大約30-40%接受化療的癌癥患者可發(fā)生粘膜炎，接受造血干細(xì)胞移植（Hematopoietic stem cell transplantation，HSCT）的患者這一比例上升到60-85%，接受放療聯(lián)合化療的頭頸部腫瘤（Head and neck cancer,HNC）患者粘膜炎的發(fā)生率上升到90%[1]。粘膜炎的程度不僅取決于抗腫瘤治療方案、劑量和給藥周期，還取決于患者自身因素。例如，女性患者在接受5-氟尿嘧啶（5-FU）治療時(shí)發(fā)生嚴(yán)重粘膜炎的風(fēng)險(xiǎn)更大[2]，與5-氟尿嘧啶分解代謝的關(guān)鍵酶二氫嘧啶脫氫酶缺乏的患者類(lèi)似[3]。然而，受異常上皮增生影響的患者，如銀屑病，粘膜炎發(fā)病率明顯降低。一般來(lái)說(shuō)，老年、女性、超重、藥物清除率降低和遺傳易感性是粘膜炎發(fā)生的風(fēng)險(xiǎn)因素。

粘膜炎的發(fā)生由一連串事件組成，這些事件可以分為五個(gè)階段，連續(xù)發(fā)生并在機(jī)制上相互關(guān)聯(lián)。粘膜損傷稱(chēng)為粘膜炎起始期，由放療和/或化療引起，與化療或放療同時(shí)發(fā)生。全身化療和放療誘導(dǎo)組織損傷，導(dǎo)致活性氧（Reactive oxygen species，ROS）釋放以及DNA損傷，從而導(dǎo)致基底和基底上皮細(xì)胞死亡[4]。特別是，DNA鏈斷裂激活細(xì)胞凋亡[5]，壞死細(xì)胞釋放內(nèi)源性損傷相關(guān)的分子模式（DAMP），是粘膜炎發(fā)生的第二階段特征，損傷的粘膜細(xì)胞促進(jìn)參與粘膜炎過(guò)程的基因轉(zhuǎn)錄包括核因子-κB（NF-κB）和促炎細(xì)胞因子（TNF-α、 L-6、IL-1β）、細(xì)胞粘附分子等 [6-7]。促炎細(xì)胞因子也存在于粘膜內(nèi)，可誘導(dǎo)結(jié)締組織和內(nèi)皮的早期損傷，并抑制組織氧化和促進(jìn)上皮基底細(xì)胞死亡。在這一階段， c-JUN和c-JUN氨基末端激酶（JNK）被激活，進(jìn)而引起細(xì)胞膜結(jié)合分子的釋放導(dǎo)致參與該過(guò)程的其他轉(zhuǎn)錄因子的激活[8]。如核因子-紅系2相關(guān)因子2（NRF2），它是一種堿性亮氨酸拉鏈蛋白，可促進(jìn)損傷和炎癥過(guò)程中抗氧化蛋白的表達(dá)[9]。此外，化療或放療也會(huì)損傷成纖維細(xì)胞，從而導(dǎo)致蛋白-1（AP1）的激活和金屬蛋白酶（MMPs）的分泌，如MMP1和MMP3，它們可降解膠原上皮下基質(zhì)和分解上皮基底膜。上述過(guò)程中產(chǎn)生的損傷反應(yīng)信號(hào)可不斷放大，在激活其他通路的同時(shí)，通過(guò)正反饋機(jī)制放大了最初的損傷。如釋放的TNF-α啟動(dòng)靶細(xì)胞上絲裂原活化蛋白激酶（MAPK）的激活，同時(shí)也可維持NF-κB的活性。在這一階段，幾次損傷會(huì)損害粘膜和粘膜下結(jié)構(gòu)。然而，患者在此階段表現(xiàn)出的癥狀很少。MAPK信號(hào)傳導(dǎo)通過(guò)JNK的激活介導(dǎo)胱天蛋白酶3的激活和細(xì)胞死亡，進(jìn)而微調(diào)AP1的轉(zhuǎn)錄活性。此外，高水平的TNF-α激活鞘磷脂酶，增加神經(jīng)酰胺途徑介導(dǎo)的促凋亡信號(hào)，并與IL-1β一起調(diào)節(jié)MMP1和MMP3的活性[10-11]。此外，受損的角蛋白細(xì)胞釋放轉(zhuǎn)化生長(zhǎng)因子β1（TGF-β1），進(jìn)而抑制細(xì)胞周期，募集白細(xì)胞并維持NF-κB活性，從而改善損傷介導(dǎo)的信號(hào)傳導(dǎo)[12]。粘膜炎的臨床表現(xiàn)在炎癥過(guò)程的第四階段，即潰瘍期是很明顯的。在此階段，粘膜和粘膜下的完整性受到破壞，患者會(huì)自述疼痛，需要進(jìn)行臨床干預(yù)。粘膜下層損傷的存在可導(dǎo)致單核細(xì)胞浸潤(rùn)介導(dǎo)的炎癥反應(yīng)，從而促進(jìn)新的促炎細(xì)胞因子的釋放，從而放大促凋亡介質(zhì)的表達(dá)并增加組織損傷[13-14]。同時(shí)化療或放療后出現(xiàn)的中性粒細(xì)胞減少癥，其持續(xù)時(shí)間長(zhǎng)和嚴(yán)重程度，患者可能會(huì)出現(xiàn)菌血癥或敗血癥，主要由鏈球菌和葡萄球菌引起[15]。粘膜炎是一種急性反應(yīng)，大多數(shù)可隨著抗腫瘤治療的結(jié)束而消退。在這個(gè)階段，愈合過(guò)程被激活，在此過(guò)程中，來(lái)自粘膜下層細(xì)胞外基質(zhì)和間充質(zhì)的刺激促進(jìn)組織上皮化[16]。

雖然目前臨床上有越來(lái)越多的新抗腫瘤藥物，但用于預(yù)防或治療粘膜炎的治療方案很少。值得注意的是，Palifermin是一種重組人角質(zhì)形成細(xì)胞生長(zhǎng)因子1（Keratinocyte growth factor 1，KGF-1），是唯一一個(gè)獲得FDA和EMA批準(zhǔn)的藥物，用于預(yù)防HSCT前接受高劑量化療加全身放療的口腔粘膜炎[17]。Palifermin可刺激上皮細(xì)胞增殖和分化，從而促進(jìn)化療和/或放療誘導(dǎo)的損傷后更快的組織再生。此外，它還具有抗氧化和抗凋亡活性以及抗促炎作用。該藥物在預(yù)防口腔粘膜炎方面的療效也在頭頸癌患者中得到了驗(yàn)證。兩項(xiàng)不同的研究表明，用Palifermin治療的患者表現(xiàn)出高級(jí)別（≥3級(jí)）口腔粘膜炎的發(fā)生率較低[18-19]，然而，該藥物的高成本和對(duì)該藥物可能會(huì)促進(jìn)腫瘤生長(zhǎng)使得其不適合用于HNC患者。此外下表中我們列舉了一些迄今為止在臨床前和臨床階段已經(jīng)證實(shí)可預(yù)防口腔粘膜炎的藥物，并根據(jù)其作用機(jī)制進(jìn)行分組。

表1根據(jù)作用機(jī)制對(duì)預(yù)防口腔粘膜炎的藥物進(jìn)行分組

抗腫瘤治療的發(fā)展顯著改善了患者的生存率。然而，盡管治療變得越來(lái)越有效，但抗腫瘤治療誘導(dǎo)的口腔粘膜炎治療或預(yù)防僅有很少的有效選擇，口腔粘膜炎通常會(huì)導(dǎo)致治療終止或需要調(diào)整治療方案，同時(shí)增加了住院率，從而增加了公共衛(wèi)生成本并降低了患者的生活質(zhì)量。通過(guò)從機(jī)制方面深入了解并匯總相關(guān)的治療方案，利于臨床醫(yī)為不同的患者設(shè)計(jì)個(gè)體化靶向治療，降低嚴(yán)重不良反應(yīng)的發(fā)生，延長(zhǎng)抗腫瘤治療的治療時(shí)間，從來(lái)改善癌癥患者的生活質(zhì)量，從而降低其管理成本。

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