A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice

Pereira, Venúcia Bruna Magalhães; Melo, Anielle Torres de; Assis-Júnior, Eudmar Marcolino; Wong, Deysi Viviana Tenazoa; Brito, Gerly A. C.; Almeida, Paulo Roberto Carvalho de; Ribeiro, Ronaldo A.; Lima-Júnior, Roberto César Pereira

doi:10.1007/s00280-015-2938-x

Cited by 26 publications

(18 citation statements)

References 39 publications

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“…Consistent with previous studies (Pereira et al, 2016 ), body weight of 5-Fu-treated mice was dramatically decreased from day 2 to day 7 after 5-Fu treatment (Figure 1A , P < 0.05 or P < 0.001), compared with the control mice. Meanwhile, severe diarrhea was found in 5-Fu group mice from day 5 to day 7 (Figure 1B , P < 0.001).…”

Section: Resultssupporting

confidence: 92%

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

Liu

Wang

et al. 2017

Front. Cell. Infect. Microbiol.

134

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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: Resultssupporting

confidence: 92%

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

Liu

Wang

et al. 2017

Front. Cell. Infect. Microbiol.

134

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“…The CPT-11-induced intestinal damage is indicated in the current work by shortened villi, loss of crypts architecture, and intense inflammatory cell infiltrate, in accordance with previous studies described in the literature [9, 10, 27, 28]. The participation of neutrophils and macrophages in the pathogenesis of CPT-11-induced intestinal mucositis had been reported [9, 10].…”

Section: Resultssupporting

confidence: 90%

“…The mast cell-mediated enhancement of inflammation could induce damage of host tissues. Accordingly, we detected that overall intestinal architecture and villi height were noticeably preserved in the group pretreated with compound 48/80, associated with decreased levels of TNF-α, IL-6, and iNOS gene expression, whose role in the chemotherapy-induced intestinal mucositis had been previously confirmed [8, 11, 27]. Consistently, the pre-degranulation of mast cells by compound 48/80 in models of lethal sepsis resulted in a significant decrease in the serum levels of TNF-α and interleukin-8 (IL-8) [24].…”

Section: Resultsmentioning

confidence: 95%

The involvement of mast cells in the irinotecan-induced enteric neurons loss and reactive gliosis

Nogueira

Costa

Gomes

et al. 2017

J Neuroinflammation

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BackgroundThe irinotecan (CPT-11) causes intestinal mucositis and diarrhea that may be related to changes in the enteric nervous system (ENS). In inflammatory condition, mast cells release a variety of pro-inflammatory mediators that can interact with the ENS cells. It has not been explored whether CPT-11 is able to alter the enteric glial and neuronal cell, and the role of mast cells in this effect. Therefore, this study was conducted to investigate the effect of CPT-11 on the enteric glial and neuronal cells, as well as to study the role of mast cells in the CPT-11-induced intestinal mucositis.MethodsIntestinal mucositis was induced in Swiss mice by the injection of CPT-11 (60 mg/kg, i.p.) once a day for 4 days following by euthanasia on the fifth day. To investigate the role of mast cells, the mice were pretreated with compound 48/80 for 4 days (first day, 0.6 mg/kg; second day, 1.0 mg/kg; third day, 1.2 mg/kg; fourth day, 2.4 mg/kg) to induce mast cell degranulation before the CPT-11 treatment.ResultsHere, we show that CPT-11 increased glial fibrillary acidic protein (GFAP) and S100β gene and S100β protein expressions and decreased HuC/D protein expression in the small intestine segments. Concomitantly, CPT-11 enhanced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels and inducible nitric oxide synthase (iNOS) gene expression, associated with an increase in the total number macrophages (positive cells for ionized calcium-binding adapter molecule, Iba-1) and degranulated mast cells in the small intestine segments and caused significant weight loss. The pretreatment with compound 48/80, an inductor of mast cells degranulation, significantly prevented these CPT-11-induced effects.ConclusionsOur data suggests the participation of mast cells on the CPT-11-induced intestinal mucositis, macrophages activation, enteric reactive gliosis, and neuron loss.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0854-1) contains supplementary material, which is available to authorized users.

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“…It had been proposed that chemotherapy drugs cause DNA and non-DNA damage to the epithelium cells, generating reactive oxygen species, and then following with the pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) being upregulated rapidly [23]. TNF-α and IL-1β play an important role in the aggravation of intestinal mucositis [24]. Our results demonstrated that the supplement of B. infantis decrease the high level of pro-inflammatory cytokines caused by chemotherapy in CRC rats.…”

Section: Discussionmentioning

confidence: 99%

Bifidobacterium Infantis Ameliorates Chemotherapy-Induced Intestinal Mucositis Via Regulating T Cell Immunity in Colorectal Cancer Rats

Dong

Zhang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Intestinal mucositis (IM) is a commonly encountered side effect in cancer patients receiving chemotherapy. This study aimed to investigate the effect of Bifidobacterium infantis (B. infantis) in attenuating the severity of chemotherapy-induced intestinal mucositis by regulating the T cell subsets in rats with colorectal cancer (CRC). Methods: Thirty male Sprague-Dawley (SD) rats were injected dimethyl hydrazine (DMH) subcutaneously for 10 weeks, and then injected SW480 cells in rectal mucosa to create a CRC model, and the rats were randomly divided into three groups: Control group (saline + saline), Chemotherapy group (saline + 5-FU+Oxaliplatin), B. infantis group (B. infantis + 5-FU+Oxaliplatin). IM was evaluated based on diarrhea severity, intestinal villus height, crypt depth, pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), T cell subsets (CD4⁺ IL17A⁺ cells and CD4⁺ CD25⁺ Foxp3⁺ Tregs) and related cytokine profiles. Results: The results showed that the B. infantis group demonstrated a higher body weight (BW) and intestinal villus height and a deeper crypt depth compared to the Chemotherapy group. The level of IL-6, IL-1β and TNF-α which increased by chemotherapy, was lowered by B. infantis administration. Real time reverse transcription- polymerase chain reaction (RT-PCR) showed B. infantis reduced relative expression of Th17 and Th1 cells related cytokines, and increased relative expression of CD4⁺ CD25⁺ Foxp3⁺ Tregs related cytokines. Furthermore, Flow cytometry analysis showed B. infantis reduced CD4⁺ IL17A⁺ cells and increased CD4⁺ CD25⁺ Foxp3⁺ Tregs in mesenteric lymph nodes (MLNs) compared to the Chemotherapy group. Conclusion: B. infantis effectively attenuates chemotherapy-induced intestinal mucositis by decreasing Th1 and Th17 response and increasing CD4⁺ CD25⁺ Foxp3⁺ Tregs response.

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A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice

Abstract: We developed a new experimental model of IM induced by combining irinotecan and 5-FU treatments, which will allow us to gain a better knowledge concerning the pathogenesis of this disease through the pharmacological modulation of key inflammatory mediators.

Cited by 26 publications

References 39 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

The involvement of mast cells in the irinotecan-induced enteric neurons loss and reactive gliosis

Bifidobacterium Infantis Ameliorates Chemotherapy-Induced Intestinal Mucositis Via Regulating T Cell Immunity in Colorectal Cancer Rats

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