In Vivo Effects of Immunomodulators in a Murine Model of Fluorouracil-Induced Mucositis

Tung, David; Cheung, Peter H.; Tudor, Gregory; Booth, Catherine; Saha, Saurabh

doi:10.1016/j.curtheres.2011.11.003

Cited by 22 publications

(16 citation statements)

References 30 publications

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“…NF-κB and MAPK pathways can be activated by many inflammatory chemokines/cytokines, which may result in a pro-inflammatory chemokines/cytokines positive feedback (Zimmerman et al, 2008 ; Tung et al, 2011 ; Chang et al, 2012 ; Jiang et al, 2012 ; Song et al, 2013 ; Candela et al, 2014 ; Dou et al, 2014 ; Yeung et al, 2015 ). And their activation in the small intestine has been shown to be involved in 5-Fu induced mucositis (Liu et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Healthy gastrointestinal microbiota characterized by high rich and diverse bacteria (Vandeputte et al, 2016 ) interacts with mucosal epithelium and is responsible for normal substance metabolism, immune response and intestinal angiogenesis (Stringer et al, 2009a , b ; Candela et al, 2014 ). Disturbed gut microbiota has been revealed to induce many disorders, such as metabolic diseases (obesity and diabetes) (Philippot et al, 2013 ), inflammatory bowel diseases (Tung et al, 2011 ), multiple sclerosis, and even psychiactric diseases such as depression (Wang and Kasper, 2014 ). More and more evidences suggest that sustained homeostasis of gut microbiota seems to benefit the recovery of many diseases.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis

Liu

Wang

et al. 2017

Front. Cell. Infect. Microbiol.

127

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Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu) induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5-Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1) and junctional adhesion molecule-A (JAM-A) were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-κB and mitogen activated protein kinase (MAPKs) in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal mucositis by manipulating gut microbiota homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis

Liu

Wang

et al. 2017

Front. Cell. Infect. Microbiol.

127

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“…23 In another cyclosporine mice study, etanercept, a TNF-a inhibitor, did not improve weight loss and diarrhea, despite decreasing gut epithelium apoptosis. 24 A likely explanation for this phenomenon is that there exists other parallel cytokine pathways to induce IL-1b plays a crucial role in the activation of the NF-kB pathway, even working with TNF for a synergistic effect in kickstarting inflammatory response of endothelial adhesion molecules. 25 Blocking the action of IL-1 via IL-1Ra in vivo has been shown to reduce mice mortality, body weight loss, and diarrhea severity.…”

Section: Cytokines Analysismentioning

confidence: 99%

SCID/NOD mice model for 5-FU induced intestinal mucositis: Safety and effects of probiotics as therapy

Huang

Chiau

Cheng

et al. 2019

Pediatrics & Neonatology

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“…5-FU has also been proposed to interfere with the activity of ribosomal RNA binding protein, at the level of pre-ribosomal RNA processing [6] . The exact mechanisms of inflammation are not fully understood, yet some progress has been made over the last several years with the development of rat, hamster [7] and mouse [8] , [9] , [10] , [11] mucositis models. Current intraperitoneal (IP) mouse models are either based on a single high dose of 5-FU (100–500 mg/kg), or a smaller daily dose (30–50 mg/kg) [10] , [11] , [12] for up to 4 weeks.…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy Induces Oral Mucositis in Mice Without Additional Noxious Stimuli

Bertolini

Sobue

Thompson

et al. 2017

Translational Oncology

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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.

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In Vivo Effects of Immunomodulators in a Murine Model of Fluorouracil-Induced Mucositis

Cited by 22 publications

References 30 publications

Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis

Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis

SCID/NOD mice model for 5-FU induced intestinal mucositis: Safety and effects of probiotics as therapy

Chemotherapy Induces Oral Mucositis in Mice Without Additional Noxious Stimuli

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