Effects of ceramide inhibition on experimental radiation-induced oral mucositis
Effects of ceramide inhibition on experimental radiation-induced oral mucositis
复制标题
DOI：
10.1016/j.tripleo.2004.09.018
复制
发表时间：
2005-09-01
期刊：
影响因子：
--
通讯作者：
Sonis, ST
中科院分区：
文献类型：
--
作者：
Hwang, D;Popat, R;Sonis, ST
目标。口腔粘膜炎(OM)是电离辐射(IR)治疗头颈部癌症的一种常见毒性。神经酰胺介导的细胞凋亡可能参与了粘膜炎的发病机制。作为对IR或其他细胞压力的响应，神经酰胺的产生要么通过鞘磷脂酶(SMase)的水解性作用，要么通过神经酰胺合成从头开始。雄性叙利亚金黄地鼠(每组10只)接受40Gy射线单次电离辐射(第0天)，从第1天到第16天分别皮下注射中性SMASE、酸性SMASE和神经酰胺合成酶抑制剂(分别为5 mM/L谷胱甘肽、5 mU/L地塞帕明和1 mU/L伏马菌素B-1)0.2mL。对照组注射生理盐水。两名盲检人员评估了从第6天到第26天的临床OM发展情况。于第3、10、16天每组各处死2只动物，免疫组织化学检测上皮和结缔组织中神经酰胺的表达。与对照组相比，暴露于伏马菌素131的组在第3天的平均日增重、平均粘膜炎评分、粘膜炎持续时间以及上皮和结缔组织中神经酰胺的表达均显著低于对照组。免疫组织化学分析还显示，与对照组相比，在第3天和第16天，接受谷胱甘肽治疗的动物上皮组织和结缔组织中神经酰胺的表达都有显著差异。这些结果表明，IR触发了早期从头神经酰胺的产生，抑制这一过程在临床水平上减轻了OM。
Objective. Oral mucositis (OM) is a common toxicity of ionizing radiation (IR), which is used as treatment for head and neck cancer. Ceramide-mediated apoptosis may contribute to the pathogenesis of mucositis. In response to IR or other cellular stresses, ceramide production occurs either by the hydrolytic action of sphingomyelinase (SMase) or de novo via ceramide synthase.Study design. Male golden Syrian hamsters (10 per group) exposed to a single dose of 40 Gy ionizing radiation (day 0) were treated with subcutaneous 0.2 mL injections of either neutral SMase, acidic SMase, or ceramide synthase inhibitor (5 mmol/L glutathione, 5 mu mol/L desipramine, or 1 mu mol/L fumonisin B-1, respectively) from day -1 to day 16. A control group was treated with saline. Two blinded examiners assessed clinical OM development from day 6 to day 26. Two animals per group were killed on days 3, 10, and 16 for immunohistochemical detection of ceramide expression in both the epithelium and in the connective tissue.Results. The group exposed to fumonisin 131 exhibited a statistically significant reduction in mean daily weight gain, mean mucositis score, duration of mucositis, and expression of ceramide in the epithelium on day 3 as well as in the connective tissue on days 10 and 16 relative to control. Immunohistologic analysis also revealed significant differences in ceramide expression on days 3 and 16 for animals treated with glutathione in both the epithelial and connective tissue when compared to the control.Conclusions. These results suggest that IR triggers early de novo ceramide production and that inhibition of this process attenuates OM on a clinical level.