The online version of this article (doi:10.1186/s12974-017-0854-1) contains supplementary material, which is available to authorized users.
The 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.
Intestinal 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.
Here, 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.
Our data suggests the participation of mast cells on the CPT-11-induced intestinal mucositis, macrophages activation, enteric reactive gliosis, and neuron loss.
Additional file 1: CPT-11 increases the number of mast cells in the small intestine. Intestinal segments (duodenum, jejunum or ileum) were stained with toluidine blue. Mast cells (black arrows) were counted in all intestinal segments. Scale bar = 50 μm. (TIF 3590 kb)12974_2017_854_MOESM1_ESM.tif
Additional file 2: Mast cell pre-degranulation prevents CPT-11-induced increase of tryptase immunostainedcells in the duodenum and jejunum of mice. Graph represents the mean ± SEM of the number of tryptasepositive cells in the duodenum, and jejunum in ten microsc opic field per section from four mice in eachgroup. White, black and crosshatch bars represent, respectively control, CPT-11 and CPT-11+c48/80 group.#P < 0.05 versus control group. *P < 0.05 versus CPT-11 group. One-way ANOVA followed by Bonferroni. (DOC 70 kb)12974_2017_854_MOESM2_ESM.doc
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- The involvement of mast cells in the irinotecan-induced enteric neurons loss and reactive gliosis
Ludmila T. Nogueira
Deiziane V. S. Costa
Antoniella S. Gomes
Conceição S. Martins
Angeline M. H. P. Silva
Juliana M. Coelho-Aguiar
Roberto C. P. Lima-Júnior
Renata F. C. Leitão
Gerly A. C. Brito
- BioMed Central