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放射性皮肤损伤(radiation-induced skin injury,RISI)是放疗患者最常见的并发症之一,若不采取保护措施,RISI的发生率可达90%以上。轻度RISI无需治疗即可自愈,重度RISI可能会引起难以愈合的创面坏死、溃疡,从而使得患者被迫停止放疗。
随着核能技术的不断发展和同位素技术的广泛应用,核与辐射事故发生的概率增加。RISI的早期症状包括红斑、水泡、脱发、黏膜炎、结膜炎、表皮剥落和溃疡等;晚期症状包括皮肤毛细血管扩张、指(趾)甲下线状出血、表皮萎缩、弥漫性角化病、皮肤和皮下纤维化伴有局部溃疡等[1]。
目前普遍认为RISI的发生机制与辐射诱导的活性氧(reactive oxygen species,ROS)生成、炎症反应和先天性免疫反应有关[2]。根据药物作用机制和结构类型不同,我们对近年来RISI防治药物的研究进展进行分类综述。
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中医认为RISI是由于热邪伤阴引起热蕴肌腠,从而导致患者脱屑、瘙痒、溃疡等症,血热起红斑,血瘀至色素沉着,气血凝滞,在防治上以清热解毒,消炎止痛为原则。 周欢欢等[34]的临床研究结果表明,清热解毒方对RISI具有明显的治疗作用。
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Yu等[35]通过随机对照双盲临床试验结果证实,黄连解毒膏能有效治疗RISI,降低Ⅲ级以上RISI的发病率,提高RISI的临床治疗效果。 Wang等[36]的体内外试验结果显示,黄连解毒膏降低了炎症细胞因子IL-1β、IL-6、TNF-α和表皮损伤相关因子整合素β1、趋化因子配体9(CXCL-9)、细胞角蛋白17的表达水平,并显著下调了高迁移率族蛋白B1(HMG-B1)的表达水平。
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淫羊藿是一种传统中药,因其具有补肾阳、祛风湿、强筋骨的功效,常被用作补药。淫羊藿素是从中药淫羊藿中提取、分离得到的淫羊藿苷水解产物。淫羊藿素不仅具有促进骨骼修复和消炎等作用,还可影响多种免疫细胞的活性,临床上可作为一种新的免疫调节剂用于肝癌的治疗。王锃等[37]研究了淫羊藿素对人角质形成细胞HaCat辐射损伤的保护作用,HaCat细胞经20 Gy的X射线照射后,细胞存活率下降、凋亡率升高,给予淫羊藿素处理后,HaCat细胞的增殖和存活能力均得到提高,细胞凋亡率、细胞内ROS和丙二醛的水平均降低,从而减轻了氧化应激反应;同时HaCat细胞中炎症因子IL-lβ、IL-6以及TNF-a的表达水平降低。这表明,淫羊藿素对人角质形成细胞HaCat存在明显的辐射保护作用,具有促进细胞增殖、抑制细胞凋亡、抗氧化和抗炎的功效。
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白芷芦荟凝胶可在一定程度上改善急性RISI患者的疼痛、瘙痒等临床症状[38]。刘燕和秦亚辉[39]采用芦荟硅霜防治鼻咽癌RISI,在照射剂量为20 Gy时,预防组发生Ⅰ、Ⅱ级RISI的例数及百分比均显著低于治疗组,且放疗结束时预防组未发生Ⅲ级RISI,而治疗组有4例;预防组较治疗组平均治愈时间缩短2~3 d。这表明芦荟硅霜对RISI有一定的预防和治疗作用,放疗前使用效果更好。Wang等[40]的研究结果显示,芦荟预处理组与未使用芦荟的对照组相比,服用芦荟的患者患RISI的可能性更小。因此芦荟的预防性应用可能显著降低RISI的发生率,尤其是Ⅱ级和Ⅲ级RISI。
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金盏花作为民间草药,具有平肝清热、祛风、化痰、抗炎和促进伤口愈合等功效。金盏花软膏有助于减轻炎症,促进皮肤再生,并缓解RISI的症状 [41]。 此外,接受金盏花治疗的患者RISI疼痛程度较轻,很少中断放疗,这在最近的一项随机试验中已得到证实[42]。
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姜黄素是从多年生草本植物姜黄中提取的一种多酚类化合物,具有多种药理活性。Ostadi等[43]的荟萃分析研究结果显示,姜黄素能减轻RISI的严重程度。有必要进一步进行大规模的前瞻性试验,以确定用于RISI防治的姜黄素的给药形式和剂量。
综上,RISI防治药物及其作用机制见表1。
类型 名称 作用机制 研究者 抗氧化剂 CPh-1014 清除自由基 Clémenson等[3] SOD 催化超氧阴离子自由基歧化生成氧和过氧化氢,清除自由基 李雪[4] Tempol 与SOD的作用类似 Metz等[5] NAC 减少脂质过氧化,清除自由基 Tascilar等[6] 含氢气体(1.3%氢气+20.8%
氧气+77.9%氮气)抗氧化、抗炎 周平等[7]和Watanabe等[8] EGCG 抗炎、抗氧化、抗感染 Zhao等[9] 维生素E纳米颗粒乳膏 抗氧化 Schmidt等 [10] 抗炎剂 皮质类固醇 抗炎,减少辐射诱导的细胞因子的释放 Haruna等[11]和Ho等[12] 三乙醇胺 渗透和毛细作用 袁芳等[13]和Elliott等[14] 老药新用 非诺贝特 激活过氧化物酶体增殖物激活受体 Sun等[15] 2-甲氧基雌二醇 抑制内皮细胞中HIF-1α表达 Kim等[16] 去铁胺 铁螯合剂,上调诱导型一氧化氮合酶和增加一氧化氮生成 Shen等[17]和Lintel等[18] 替马洛尔 β-肾上腺素能受体拮抗剂,在皮肤细胞和角质细胞迁移中发挥作用和抗炎作用 Nabi-Meybodi等[19] 己酮可可碱 抗炎、免疫调节、血管调节、抗纤维化 Wang和Tepper[20] 新型辅料 K16 清除ROS,防止辐射对细胞DNA的损伤,促进细胞增殖、迁移和血管生成,吸附炎症细胞因子 Hao等[21] GK@TAgel 清除ROS,驱动M2巨噬细胞极化 Feng等[22] 表 1 放射性皮肤损伤防治药物及其作用机制
Table 1. Drugs for prevention and treatment of radiation-induced skin injury and their mechanisms
续表 1 放射性皮肤损伤防治药物及其作用机制 Continue Table 1 Drugs for prevention and treatment of radiation-induced skin injury and their mechanisms 类型 名称 作用机制 研究者 生长因子 表皮生长因子 促进DNA、RNA和羟脯氨酸的合成,促进鳞状上皮细胞和血管内皮细胞的生长 Kang 等[23]和Liu等[24] FGF 刺激新生血管形成 Kinoda 等[25] 干细胞 骨髓间充质干细胞 多向分化、促血管生成、分泌生长因子 Fang等[27]和Kakabadze等[28] 脂肪干细胞 多向分化、分泌细胞因子和免疫豁免 Wu 等[29]和Zhang等[30] 脐带间充质干细胞 多向分化、促血管生成、分泌生长因子 Guo等[31]和Fang等[32] 基质血管组分 具有干细胞的特性,促进组织的修复和再生 Yu等[33] 中草药 清热解毒方(大黄、黄连、黄芩、地榆、红花) 清热解毒、消炎止痛 周欢欢等[34] 黄连解毒膏(黄连、黄柏、黄芩、紫草) 清热解毒、消炎止痛 Yu 等[35] 和Wang等[36] 淫羊藿 免疫调节、抗炎、清除ROS 王锃等[37] 芦荟 杀菌消炎、增强免疫功能、清除自由基 王晶和雷振宇[38]、刘燕和秦亚辉[39]、Wang等[40] 金盏花 抗菌、消炎 Gilca等[41]和Schneider等[42] 姜黄素 抗氧化、抗炎 Ostadi等[43] 注:CPh-1014为一种含氨磷汀代谢产物活性硫醇的热凝胶;SOD为超氧化物歧化酶;Tempol为一种SOD类似物;NAC为N-乙酰半胱氨酸;EGCG为表没食子儿茶素没食子酸酯;HIF-1α为缺氧诱导因子1α;K16为一种具有抗氧化活性、仿肝素的肽水凝胶;ROS为活性氧;GK@TAgel为一种细胞外基质激发的糖肽水凝胶;FGF为成纤维细胞生长因子
放射性皮肤损伤防治药物的研究进展
Research progress of drugs for prevention and treatment of radiation-induced skin injury
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摘要: 皮肤是人体最大的器官,在肿瘤放疗或意外照射事故中,皮肤会受到不同剂量的辐射,造成放射性皮肤损伤(RISI)。临床上对RISI的治疗主要采取对症治疗,缺乏有效的针对性药物,因此研究安全、有效的RISI防治药物极为重要。笔者总结了近年来国内外RISI防治药物的研究进展,旨在为RISI防治药物的研究提供参考。Abstract: The skin is the largest organ of the human body. In tumor radiotherapy or accidental radiation accidents, the skin will receive different doses of radiation, resulting in radiation-induced skin injury (RISI). Clinical treatment of RISI is mainly symptomatic treatment, lack of effective targeted drugs. Therefore, it is very important to study safe and effective drugs for the prevention and treatment of RISI. This paper reviews the research progress of RISI prevention and treatment drugs at home and abroad in recent years, in order to provide reference for the research of RISI prevention and treatment drugs.
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Key words:
- Radiation injuries /
- Skin /
- Radiation-protective agents
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表 1 放射性皮肤损伤防治药物及其作用机制
Table 1. Drugs for prevention and treatment of radiation-induced skin injury and their mechanisms
类型 名称 作用机制 研究者 抗氧化剂 CPh-1014 清除自由基 Clémenson等[3] SOD 催化超氧阴离子自由基歧化生成氧和过氧化氢,清除自由基 李雪[4] Tempol 与SOD的作用类似 Metz等[5] NAC 减少脂质过氧化,清除自由基 Tascilar等[6] 含氢气体(1.3%氢气+20.8%
氧气+77.9%氮气)抗氧化、抗炎 周平等[7]和Watanabe等[8] EGCG 抗炎、抗氧化、抗感染 Zhao等[9] 维生素E纳米颗粒乳膏 抗氧化 Schmidt等 [10] 抗炎剂 皮质类固醇 抗炎,减少辐射诱导的细胞因子的释放 Haruna等[11]和Ho等[12] 三乙醇胺 渗透和毛细作用 袁芳等[13]和Elliott等[14] 老药新用 非诺贝特 激活过氧化物酶体增殖物激活受体 Sun等[15] 2-甲氧基雌二醇 抑制内皮细胞中HIF-1α表达 Kim等[16] 去铁胺 铁螯合剂,上调诱导型一氧化氮合酶和增加一氧化氮生成 Shen等[17]和Lintel等[18] 替马洛尔 β-肾上腺素能受体拮抗剂,在皮肤细胞和角质细胞迁移中发挥作用和抗炎作用 Nabi-Meybodi等[19] 己酮可可碱 抗炎、免疫调节、血管调节、抗纤维化 Wang和Tepper[20] 新型辅料 K16 清除ROS,防止辐射对细胞DNA的损伤,促进细胞增殖、迁移和血管生成,吸附炎症细胞因子 Hao等[21] GK@TAgel 清除ROS,驱动M2巨噬细胞极化 Feng等[22] 续表 1 放射性皮肤损伤防治药物及其作用机制 Continue Table 1 Drugs for prevention and treatment of radiation-induced skin injury and their mechanisms 类型 名称 作用机制 研究者 生长因子 表皮生长因子 促进DNA、RNA和羟脯氨酸的合成,促进鳞状上皮细胞和血管内皮细胞的生长 Kang 等[23]和Liu等[24] FGF 刺激新生血管形成 Kinoda 等[25] 干细胞 骨髓间充质干细胞 多向分化、促血管生成、分泌生长因子 Fang等[27]和Kakabadze等[28] 脂肪干细胞 多向分化、分泌细胞因子和免疫豁免 Wu 等[29]和Zhang等[30] 脐带间充质干细胞 多向分化、促血管生成、分泌生长因子 Guo等[31]和Fang等[32] 基质血管组分 具有干细胞的特性,促进组织的修复和再生 Yu等[33] 中草药 清热解毒方(大黄、黄连、黄芩、地榆、红花) 清热解毒、消炎止痛 周欢欢等[34] 黄连解毒膏(黄连、黄柏、黄芩、紫草) 清热解毒、消炎止痛 Yu 等[35] 和Wang等[36] 淫羊藿 免疫调节、抗炎、清除ROS 王锃等[37] 芦荟 杀菌消炎、增强免疫功能、清除自由基 王晶和雷振宇[38]、刘燕和秦亚辉[39]、Wang等[40] 金盏花 抗菌、消炎 Gilca等[41]和Schneider等[42] 姜黄素 抗氧化、抗炎 Ostadi等[43] 注:CPh-1014为一种含氨磷汀代谢产物活性硫醇的热凝胶;SOD为超氧化物歧化酶;Tempol为一种SOD类似物;NAC为N-乙酰半胱氨酸;EGCG为表没食子儿茶素没食子酸酯;HIF-1α为缺氧诱导因子1α;K16为一种具有抗氧化活性、仿肝素的肽水凝胶;ROS为活性氧;GK@TAgel为一种细胞外基质激发的糖肽水凝胶;FGF为成纤维细胞生长因子 -
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