5-Fluorouracil Induced Intestinal Mucositis via Nuclear Factor-κB Activation by Transcriptomic Analysis and In Vivo Bioluminescence Imaging
5-Fluorouracil Induced Intestinal Mucositis via Nuclear Factor-κB Activation by Transcriptomic Analysis and In Vivo Bioluminescence Imaging
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DOI：
10.1371/journal.pone.0031808
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发表时间：
2012-03-07
期刊：
影响因子：
3.7
通讯作者：
Hsiang, Chien-Yun
中科院分区：
文献类型：
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作者：
Chang, Chung-Ta;Ho, Tin-Yun;Hsiang, Chien-Yun
5-氟尿嘧啶（5-FU）是一种常用的治疗恶性肿瘤的药物。然而，大约80%接受5-FU治疗的患者患有胃肠道粘膜炎。本报告的目的是确定5-FU诱导的肠粘膜炎的药物靶点。通过腹腔注射100 mg/kg 5-FU建立5-FU诱导的肠粘膜炎。应用基因表达谱的网络分析和生物发光成像来鉴定与5-FU诱导的粘膜炎相关的关键分子。我们的数据表明，5-FU诱导小肠炎症，其特征在于肠壁厚度和隐窝长度增加，绒毛高度降低，组织中髓过氧化物酶活性和血清中促炎细胞因子产生增加。利用转录组学工具对5-FU作用的基因进行网络分析，结果表明基因表达受核因子-κ B（NF-κ B B）调控，NF-κ B B是5-FU调控的生物网络的中心分子。通过体内生物发光成像和免疫组织化学染色判断，5-FU激活了肠内NF-κ B活性。然而，5-氨基水杨酸（5-阿萨）抑制5-FU诱导的NF-κ B活化和促炎细胞因子的产生。此外，5-ASA可改善5-FU引起的组织学改变。结论：NF-κ B B是5-FU诱导的黏膜炎发病机制的关键分子，抑制NF-κ B B活性可减轻5-FU引起的黏膜损伤。
5-Fluorouracil (5-FU) is a commonly used drug for the treatment of malignant cancers. However, approximately 80% of patients undergoing 5-FU treatment suffer from gastrointestinal mucositis. The aim of this report was to identify the drug target for the 5-FU-induced intestinal mucositis. 5-FU-induced intestinal mucositis was established by intraperitoneally administering mice with 100 mg/kg 5-FU. Network analysis of gene expression profile and bioluminescent imaging were applied to identify the critical molecule associated with 5-FU-induced mucositis. Our data showed that 5-FU induced inflammation in the small intestine, characterized by the increased intestinal wall thickness and crypt length, the decreased villus height, and the increased myeloperoxidase activity in tissues and proinflammatory cytokine production in sera. Network analysis of 5-FU-affected genes by transcriptomic tool showed that the expression of genes was regulated by nuclear factor-kappa B (NF-kappa B), and NF-kappa B was the central molecule in the 5-FU-regulated biological network. NF-kappa B activity was activated by 5-FU in the intestine, which was judged by in vivo bioluminescence imaging and immunohistochemical staining. However, 5-aminosalicylic acid (5-ASA) inhibited 5-FU-induced NF-kappa B activation and proinflammatory cytokine production. Moreover, 5-FU-induced histological changes were improved by 5-ASA. In conclusion, our findings suggested that NF-kappa B was the critical molecule associated with the pathogenesis of 5-FU-induced mucositis, and inhibition of NF-kappa B activity ameliorated the mucosal damage caused by 5-FU.