Chemotherapy Induces Oral Mucositis in Mice Without Additional Noxious Stimuli

Abstract

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.

Lactobacillus reuteri DSM 17938 and ATCC PTA 5289 ameliorates chemotherapy-induced oral mucositis

“…In this study, 5-FU, a common anti-neoplastic drug was used to induce OM 25 . The primary mechanism of 5-FU's action is through complexing with thymidylate synthase, an essential enzyme in DNA biosynthesis which disrupts DNA synthesis, thus triggering the production of highly reactive hydroxyl and superoxide radicals 26 .…”

Management of oral mucositis in pediatric patients receiving cancer therapy: A systematic review and meta‐analysis

“…7,8 Oral and gastrointestinal mucosa inflammation can cause severe ulcers, infections, and problems or shortcomings in basic tasks like swallowing or consuming foods or drinks. OM also has a major impact on quality of life and nutritional status, prolonged hospital stays, and [9][10][11] For all these reasons, it is crucial that OM be prevented or treated as quickly as possible.…”

The Dysbiosis and Inter-Kingdom Synergy Model in Oropharyngeal Candidiasis, a New Perspective in Pathogenesis

“…The type of immunosuppression can play a decisive role in modifying the local microbial environment where C. albicans infections occur, since different types of immune deficiencies may drive qualitatively different bacterial community shifts. For example, mice given cortisone have an increased number of functionally competent infiltrating neutrophils, whereas mice given cytotoxic chemotherapy are severely neutropenic [12,13,45,46]. It is thus possible that bacteria that are primarily cleared by neutrophils overgrow during cytotoxic chemotherapy treatment, whereas neutrophil-resistant bacteria are more likely to survive during chronic use of corticosteroids.…”

“…In immunocompromised hosts indigenous bacterial species that form mutualistic relationships with C. albicans may increase in abundance leading to a well-coordinated dysbiosis which amplifies mucosal damage. To support this concept, we conducted experiments using a cytotoxic cancer chemotherapy model, which recapitulates oral mucosal and bone marrow toxicity in cancer patients receiving 5-FU [45]. When C. albicans is orally inoculated indigenous oral bacterial burdens rise in parallel with fungal burdens in mice receiving 5-FU [12], making the model ideal for the study of the role of resident oral bacteria in fungal pathogenesis.…”