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

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Our data suggests the participation of mast cells on the CPT-11-induced intestinal mucositis, macrophages activation, enteric reactive gliosis, and neuron loss.

Electronic supplementary material: The online version of this article (doi:10.1186/s12974-017-0854-1) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Pre-degranulation of mast cells reduces inflammation in duodenum and jejunum and weight loss of mice submitted to CPT-11-induced intestinal mucositis. a Pretreatment with c48/80 diminishes TNF-α levels in duodenum and jejunum of mice submitted to CPT-11-induced intestinal mucositis. b Pretreatment with c48/80 diminishes IL-6 levels in duodenum and jejunum of mice submitted to CPT-11-induced intestinal mucositis. c Pretreatment with c48/80 decreases iNOS mRNA expression in mice submitted to CPT-11-induced intestinal mucositis. Bars represent mean ± SEM of six mice in each group. #p < 0.05 versus control group, *p < 0.05 versus CPT-11 group. One-way ANOVA followed by Bonferroni. d Body weight changes are shown as percentages of the baseline value. Bars represent mean ± SEM of six mice in each group. #p < 0.05 versus control group, *p < 0.05 versus CPT-11 group. Two-way ANOVA followed by Bonferroni
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC5384042&req=5

Fig4: Pre-degranulation of mast cells reduces inflammation in duodenum and jejunum and weight loss of mice submitted to CPT-11-induced intestinal mucositis. a Pretreatment with c48/80 diminishes TNF-α levels in duodenum and jejunum of mice submitted to CPT-11-induced intestinal mucositis. b Pretreatment with c48/80 diminishes IL-6 levels in duodenum and jejunum of mice submitted to CPT-11-induced intestinal mucositis. c Pretreatment with c48/80 decreases iNOS mRNA expression in mice submitted to CPT-11-induced intestinal mucositis. Bars represent mean ± SEM of six mice in each group. #p < 0.05 versus control group, *p < 0.05 versus CPT-11 group. One-way ANOVA followed by Bonferroni. d Body weight changes are shown as percentages of the baseline value. Bars represent mean ± SEM of six mice in each group. #p < 0.05 versus control group, *p < 0.05 versus CPT-11 group. Two-way ANOVA followed by Bonferroni

Mentions: In order to reinforce that the mast cell pre-degranulation could be able to prevent the CPT-11-induced inflammation, we assessed the levels of TNF-α and IL-6 in the duodenum and jejunum. We found that the pretreatment with compound 48/80 prevented (p < 0.05) the increase in both TNF-α (Fig. 4a) and IL-6 (Fig. 4b) levels, induced by CPT-11, since significant differences were found between CPT-11 + c48/80 and CPT-11 groups. Moreover, the pretreatment with compound 48/80 prevented the increase in the iNOS genic expression, induced by CPT-11, in the duodenum (Fig. 4c). It must be noted that the administration of compound 48/80 alone (not followed by CPT-11 administrations) had no effect on the levels of TNF-α, IL-6, or iNOS genic expression in the duodenum, since no statistical differences were detected between c48/80 and control groups. On the other hand, compound 48/80 itself induced an increase in the TNF-α and IL-6 levels in the jejunum compared to the control group.Fig. 4


The involvement of mast cells in the irinotecan-induced enteric neurons loss and reactive gliosis
Pre-degranulation of mast cells reduces inflammation in duodenum and jejunum and weight loss of mice submitted to CPT-11-induced intestinal mucositis. a Pretreatment with c48/80 diminishes TNF-α levels in duodenum and jejunum of mice submitted to CPT-11-induced intestinal mucositis. b Pretreatment with c48/80 diminishes IL-6 levels in duodenum and jejunum of mice submitted to CPT-11-induced intestinal mucositis. c Pretreatment with c48/80 decreases iNOS mRNA expression in mice submitted to CPT-11-induced intestinal mucositis. Bars represent mean ± SEM of six mice in each group. #p < 0.05 versus control group, *p < 0.05 versus CPT-11 group. One-way ANOVA followed by Bonferroni. d Body weight changes are shown as percentages of the baseline value. Bars represent mean ± SEM of six mice in each group. #p < 0.05 versus control group, *p < 0.05 versus CPT-11 group. Two-way ANOVA followed by Bonferroni
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5384042&req=5

Fig4: Pre-degranulation of mast cells reduces inflammation in duodenum and jejunum and weight loss of mice submitted to CPT-11-induced intestinal mucositis. a Pretreatment with c48/80 diminishes TNF-α levels in duodenum and jejunum of mice submitted to CPT-11-induced intestinal mucositis. b Pretreatment with c48/80 diminishes IL-6 levels in duodenum and jejunum of mice submitted to CPT-11-induced intestinal mucositis. c Pretreatment with c48/80 decreases iNOS mRNA expression in mice submitted to CPT-11-induced intestinal mucositis. Bars represent mean ± SEM of six mice in each group. #p < 0.05 versus control group, *p < 0.05 versus CPT-11 group. One-way ANOVA followed by Bonferroni. d Body weight changes are shown as percentages of the baseline value. Bars represent mean ± SEM of six mice in each group. #p < 0.05 versus control group, *p < 0.05 versus CPT-11 group. Two-way ANOVA followed by Bonferroni
Mentions: In order to reinforce that the mast cell pre-degranulation could be able to prevent the CPT-11-induced inflammation, we assessed the levels of TNF-α and IL-6 in the duodenum and jejunum. We found that the pretreatment with compound 48/80 prevented (p < 0.05) the increase in both TNF-α (Fig. 4a) and IL-6 (Fig. 4b) levels, induced by CPT-11, since significant differences were found between CPT-11 + c48/80 and CPT-11 groups. Moreover, the pretreatment with compound 48/80 prevented the increase in the iNOS genic expression, induced by CPT-11, in the duodenum (Fig. 4c). It must be noted that the administration of compound 48/80 alone (not followed by CPT-11 administrations) had no effect on the levels of TNF-α, IL-6, or iNOS genic expression in the duodenum, since no statistical differences were detected between c48/80 and control groups. On the other hand, compound 48/80 itself induced an increase in the TNF-α and IL-6 levels in the jejunum compared to the control group.Fig. 4

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods: Intestinal mucositis was induced in Swiss mice by the injection of CPT-11 (60&nbsp;mg/kg, i.p.) once a day for 4&nbsp;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&nbsp;days (first day, 0.6&nbsp;mg/kg; second day, 1.0&nbsp;mg/kg; third day, 1.2&nbsp;mg/kg; fourth day, 2.4&nbsp;mg/kg) to induce mast cell degranulation before the CPT-11 treatment.

Results: Here, we show that CPT-11 increased glial fibrillary acidic protein (GFAP) and S100&beta; gene and S100&beta; protein expressions and decreased HuC/D protein expression in the small intestine segments. Concomitantly, CPT-11 enhanced tumor necrosis factor-&alpha; (TNF-&alpha;) 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.

Conclusions: Our data suggests the participation of mast cells on the CPT-11-induced intestinal mucositis, macrophages activation, enteric reactive gliosis, and neuron loss.

Electronic supplementary material: The online version of this article (doi:10.1186/s12974-017-0854-1) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus