上皮粘膜在放化療作用下發(fā)生炎癥反應可導致粘膜炎，粘膜炎可影響胃腸道和口腔，導致患者疼痛、無法進食、體重減輕甚至造成局部感染。此外，級別嚴重的粘膜炎可導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）治療時發(fā)生嚴重粘膜炎的風險更大[2]，與5-氟尿嘧啶分解代謝的關鍵酶二氫嘧啶脫氫酶缺乏的患者類似[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。一般來說，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)生的風險因素。

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階段，連續(xù)發(fā)生并在機制上相互關聯(lián)。粘膜損傷稱為粘膜炎起始期，由放療和/或化療引起，與化療或放療同時發(fā)生。全身化療和放療誘導組織損傷，導致活性氧（Reactive oxygen species，ROS）釋放以及DNA損傷，從而導致基底和基底上皮細胞死亡[4]。特別是，DNA鏈斷裂激活細胞凋亡[5]，壞死細胞釋放內源性損傷相關的分子模式（DAMP），是粘膜炎發(fā)生的第二階段特征，損傷的粘膜細胞促進參與粘膜炎過程的基因轉錄包括核因子-κB（NF-κB）和促炎細胞因子（TNF-α、 L-6、IL-1β）、細胞粘附分子等 [6-7]。促炎細胞因子也存在于粘膜內，可誘導結締組織和內皮的早期損傷，并抑制組織氧化和促進上皮基底細胞死亡。在這一階段， c-JUN和c-JUN氨基末端激酶（JNK）被激活，進而引起細胞膜結合分子的釋放導致參與該過程的其他轉錄因子的激活[8]。如核因子-紅系2相關因子2（NRF2），它是一種堿性亮氨酸拉鏈蛋白，可促進損傷和炎癥過程中抗氧化蛋白的表達[9]。此外，化療或放療也會損傷成纖維細胞，從而導致蛋白-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和分解上皮基底膜。上述過程中產生的損傷反應信號可不斷放大，在激活其他通路的同時，通過正反饋機制放大了最初的損傷。如釋放的TNF-α啟動靶細胞上絲裂原活化蛋白激酶（MAPK）的激活，同時也可維持NF-κB的活性。在這一階段，幾次損傷會損害粘膜和粘膜下結構。然而，患者在此階段表現出的癥狀很少。MAPK信號傳導通過JNK的激活介導胱天蛋白酶3的激活和細胞死亡，進而微調AP1的轉錄活性。此外，高水平的TNF-α激活鞘磷脂酶，增加神經酰胺途徑介導的促凋亡信號，并與IL-1β一起調節(jié)MMP1和MMP3的活性[10-11]。此外，受損的角蛋白細胞釋放轉化生長因子β1（TGF-β1），進而抑制細胞周期，募集白細胞并維持NF-κB活性，從而改善損傷介導的信號傳導[12]。粘膜炎的臨床表現在炎癥過程的第四階段，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，患者會自述疼痛，需要進行臨床干預。粘膜下層損傷的存在可導致單核細胞浸潤介導的炎癥反應，從而促進新的促炎細胞因子的釋放，從而放大促凋亡介質的表達并增加組織損傷[13-14]。同時化療或放療后出現的中性粒細胞減少癥，其持續(xù)時間長和嚴重程度，患者可能會出現菌血癥或敗血癥，主要由鏈球菌和葡萄球菌引起[15]。粘膜炎是一種急性反應，大多數可隨著抗腫瘤治療的結束而消退。在這個階段，愈合過程被激活，在此過程中，來自粘膜下層細胞外基質和間充質的刺激促進組織上皮化[16]。

雖然目前臨床上有越來越多的新抗腫瘤藥物，但用于預防或治療粘膜炎的治療方案很少。值得注意的是，Palifermin是一種重組人角質形成細胞生長因子1（Keratinocyte growth factor 1，KGF-1），是唯一一個獲得FDA和EMA批準的藥物，用于預防HSCT前接受高劑量化療加全身放療的口腔粘膜炎[17]。Palifermin可刺激上皮細胞增殖和分化，從而促進化療和/或放療誘導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。該藥物在預防口腔粘膜炎方面的療效也在頭頸癌患者中得到了驗證。兩項不同的研究表明，用Palifermin治療的患者表現出高級別（≥3級）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該藥物可能會促進腫瘤生長使得其不適合用于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證實可預防口腔粘膜炎的藥物，并根據其作用機制進行分組。

表1根據作用機制對預防口腔粘膜炎的藥物進行分組

抗腫瘤治療的發(fā)展顯著改善了患者的生存率。然而，盡管治療變得越來越有效，但抗腫瘤治療誘導的口腔粘膜炎治療或預防僅有很少的有效選擇，口腔粘膜炎通常會導致治療終止或需要調整治療方案，同時增加了住院率，從而增加了公共衛(wèi)生成本并降低了患者的生活質量。通過從機制方面深入了解并匯總相關的治療方案，利于臨床醫(yī)為不同的患者設計個體化靶向治療，降低嚴重不良反應的發(fā)生，延長抗腫瘤治療的治療時間，從來改善癌癥患者的生活質量，從而降低其管理成本。

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