Chemotherapy-induced oral mucositis and associated infections in a novel organotypic model.
Chemotherapy-induced oral mucositis and associated infections in a novel organotypic model.
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DOI：
10.1111/omi.12214
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发表时间：
2018-06
影响因子：
3.7
通讯作者：
Dongari-Bagtzoglou A
中科院分区：
文献类型：
--
作者：
Sobue T;Bertolini M;Thompson A;Peterson DE;Diaz PI;Dongari-Bagtzoglou A
口腔粘膜炎是癌症化疗的常见副作用，严重影响抗肿瘤治疗的效果。由于不存在相关的实验模型，对于口腔共生微生物在粘膜炎的发生或发展中的作用缺乏共识。本研究的目的是建立一种模拟化疗引起的粘膜炎的体外粘膜损伤模型，在该模型中可以研究口腔共生物的作用。基于人口腔上皮细胞系和成纤维细胞包埋的胶原基质，建立了一种新的器质性化疗所致粘膜炎模型。用5-氟尿嘧啶(5-FU)处理器官型结构后，口腔粘膜炎的主要组织病理学特征重现，如DNA合成抑制、细胞凋亡和细胞质空泡化，而不损害多层器质性黏膜的三维结构。尽管模型的结构完整性得以保留，但5-FU治疗导致上皮细胞间隙变宽，其特征是E-钙粘附素从粘连连接处溶解。在中性粒细胞迁移试验中，我们发现这种治疗促进了中性粒细胞通过上皮层的运输。此外，5-FU治疗刺激了与口腔粘膜炎发病相关的关键的促炎细胞因子。在本研究测试的条件下，5-FU处理粘膜结构对真菌或细菌生物膜的生长没有显著影响，但它加剧了对某些细菌和真菌共生体的炎症反应。这些发现表明，共生菌可能通过放大细胞毒化疗损伤的粘膜的促炎信号而在口腔粘膜炎的发病机制中发挥作用。
Oral mucositis is a common side effect of cancer chemotherapy, with significant adverse impact on the delivery of anti-neoplastic treatment. There is lack of consensus regarding the role of oral commensal microorganisms in the initiation or progression of mucositis since relevant experimental models are non-existent. The goal of this study was to develop an in vitro mucosal injury model that mimics chemotherapy-induced mucositis, where the effect of oral commensals can be studied. A novel organotypic model of chemotherapy-induced mucositis was developed based on a human oral epithelial cell line and a fibroblast-embedded collagen matrix. Treatment of organotypic constructs with 5-fluorouracil (5-FU) reproduced major histopathologic characteristics of oral mucositis, such as DNA synthesis inhibition, apoptosis and cytoplasmic vacuolation, without compromising the three-dimensional structure of the multilayer organotypic mucosa. Although structural integrity of the model was preserved, 5-FU treatment resulted in a widening of epithelial intercellular spaces characterized by E-cadherin dissolution from adherens junctions. In a neutrophil transmigration assay we discovered that this treatment facilitated transport of neutrophils through epithelial layers. Moreover, 5-FU treatment stimulated key proinflammatory cytokines that are associated with the pathogenesis of oral mucositis. 5-FU treatment of mucosal constructs did not significantly affect fungal or bacterial biofilm growth under conditions tested in this study, however it exacerbated the inflammatory response to certain bacterial and fungal commensals. These findings suggest that commensals may play a role in pathogenesis of oral mucositis by amplifying the proinflammatory signals to mucosa that is injured by cytotoxic chemotherapy.
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影响因子：
3.2
作者：
Busscher, Henk J.;van de Belt-Gritter, Betsy;van der Mei, Henny C.
通讯作者：
van der Mei, Henny C.
影响因子：
3.1
作者：
Ramla, Shilpa;Sharma, Vinay;Patel, Mrudula
通讯作者：
Patel, Mrudula
影响因子：
11.8
作者：
BOCHUD, PY;EGGIMAN, P;FRANCIOLI, P
通讯作者：
FRANCIOLI, P
影响因子：
4.8
作者：
Logan, Richard M.;Gibson, Rachel J.;Keefe, Dorothy M. K.
通讯作者：
Keefe, Dorothy M. K.
影响因子：
3.8
作者：
Li, Lulu;Kashleva, Helena;Dongari-Bagtzoglou, Anna
通讯作者：
Dongari-Bagtzoglou, Anna