Abstract
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.
Highlights
The irinotecan (CPT-11) causes intestinal mucositis and diarrhea that may be related to changes in the enteric nervous system (ENS)
CPT-11 increases the number of mast cells in the small intestine Considering that mediators released from activated mast cell are involved in neuron death [22], we investigated whether CPT-11 could increase the number of mast cells in the small intestine and induce their degranulation, using toluidine blue staining
We found that CPT-11 enhanced the total and degranulated mast cell number in the small intestine of mice subjected to CPT-11-induced intestinal mucositis when compared with the control group (Fig. 1a, Additional file 1: Figure S1)
Summary
The irinotecan (CPT-11) causes intestinal mucositis and diarrhea that may be related to changes in the enteric nervous system (ENS). 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. 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. The consequences of irinotecan in the enteric nervous system (ENS), a ganglionated neuronal network that resides within the gut wall, have not been studied and merit further investigation
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