Bertolini M, Sobue T, Thompson A, Dongari-Bagtzoglou A
University of Connecticut, Department of Oral Health and Diagnostic Sciences.
University of Connecticut, Department of Oral Health and Diagnostic Sciences.
Transl Oncol. 2017 Aug;10(4):612-620. doi: 10.1016/j.tranon.2017.05.001. Epub 2017 Jun 27.
Oral mucositis (OM) is a serious side effect of cancer chemotherapy. The pathobiology of oral mucositis remains incompletely understood due to lack of appropriate models which recapitulate the human condition. Existing rodent models are intraperitoneal and require radiation, chemical or mechanical injury to the chemotherapy protocol to induce oral lesions. We aimed to develop an OM mouse model that is induced solely by chemotherapy and reproduces macroscopic, histopathologic and inflammatory characteristics of the human condition. Female C57BL/6 mice were given intravenous 5-Fluorouracil (5-FU) injections every 48 hours, for 2 weeks. A high daily dose of intraperitoneal administration was tested for comparison. Mice were monitored daily for weight loss. Epithelial histomorphometric analyses in tongue, esophageal and intestinal tissues were conducted coupled with assessment of apoptosis, cell proliferation, neutrophilic infiltration and the integrity of adherens junctions by immunohistochemistry. Neutropenia was assessed in peripheral blood and bone marrow. Tissues were analyzed for pro-inflammatory cytokines at the protein and mRNA levels. Daily intraperitoneal administration of 5-FU led to rapid weight loss and intestinal mucositis, but no oral inflammatory changes. Intravenous administration triggered atrophy of the oral and esophageal epithelium accompanied by reduction in cell proliferation and increased apoptosis. Coincidental with these changes were up-regulation of NF-κB, TNFα, IL-1β, GM-CSF, IL-6 and KC. Despite neutropenia, increased oral neutrophilic infiltration and reduced E-cadherin was observed in oroesophageal mucosae. We developed a novel experimental tool for future mechanistic studies on the pathogenesis of chemotherapy-induced OM.
口腔黏膜炎（OM）是癌症化疗的一种严重副作用。由于缺乏能够重现人类病情的合适模型，口腔黏膜炎的病理生物学仍未被完全理解。现有的啮齿动物模型是腹腔内给药，并且在化疗方案中需要辐射、化学或机械损伤来诱导口腔病变。我们旨在开发一种仅由化疗诱导的口腔黏膜炎小鼠模型，该模型能够重现人类病情的宏观、组织病理学和炎症特征。雌性C57BL/6小鼠每48小时静脉注射5-氟尿嘧啶（5-FU），持续2周。为作比较，测试了高剂量每日腹腔给药。每天监测小鼠体重减轻情况。对舌、食管和肠道组织进行上皮组织形态计量分析，并通过免疫组织化学评估细胞凋亡、细胞增殖、中性粒细胞浸润和黏附连接的完整性。对外周血和骨髓进行中性粒细胞减少评估。分析组织中促炎细胞因子的蛋白质和mRNA水平。每日腹腔注射5-FU导致体重迅速减轻和肠道黏膜炎，但无口腔炎症变化。静脉注射引发口腔和食管上皮萎缩，伴有细胞增殖减少和细胞凋亡增加。与这些变化同时出现的是NF-κB、TNFα、IL-1β、GM-CSF、IL-6和KC的上调。尽管存在中性粒细胞减少，但在口腔食管黏膜中观察到中性粒细胞浸润增加和E-钙黏蛋白减少。我们开发了一种新的实验工具，用于未来对化疗诱导的口腔黏膜炎发病机制的机制研究。
