Modulação da resposta inflamatória com dexametasona reverte a dismotiliade gastrintestinal associada à mucosite intestinal induzida por irinotecano em camundongos

Abstract

Mucositis induced by antineoplasic drugs is a limiting factor in anticancer therapy. Mucositis is a clinical term which describes a syndrome characterized by mucosal ulceration of the entire digestive tract. Mucositis results from intestinal inflammatory events, which induces changes in gastrointestinal motility. Dexamethasone is a glucocorticoid whose main pharmacological effect is anti-inflammatory and immunosuppressive. Objectives: To investigate the gastrointestinal dismotility associated with irinotecan-induced intestinal mucositis in mice and to assess the effect of pharmacological modulation of the inflammatory response on these motor abnormalities. Methods: Swiss male mice (20-25g) were treated in the D1-D4 with irinotecan (75 mg / kg, ip) or saline (0.1 ml, ip), the sacrifice was performed on the seventh day trial in order to study changes related to intestinal mucositis. Samples of duodenum, jejunum and ileum were removed to assess the epithelial injury by morphometry, histological scores and MPO activity, and diarrhea were evaluated before sacrifice. For evaluation of cytokine samples of duodenum were removed and the ELISA was determined concentrations of TNF-, IL-1 , KC and IL-10. In order to evaluate gastrointestinal motility, the animals were kept fasting for 18 hours from D6 to D7. In D7, were administered 350μL of glucose solution (5%) containing phenol red (VF) to 0.75 mg / ml in each animal prior to sacrifice. After the times of 10, 20 and 30min, animals were sacrifice. Stomach was totally removed, and small intestine was divided into 3 parts: proximal, medial and distal. The gastric emptying, intestinal transit and gastrointestinal transit were determinate by spectrofotometry. In other experimental group, we evaluated if pharmacological modulation of the inflammatory process could reverse the gastrointestinal dismotility associated with irinotecan- induced intestinal mucositis. Then, dexamethasone (2.5 mg / kg sc) or metoclopramide (10mg/kg ip) of D1-D7 were administrated 30 minutes before irinotecan administration and all of parameters described before were evaluated Results: Treatment with irinotecan was able to induce an intestinal lesion with significant impairment of epithelial barrier function in the presence of the following changes: diarrhea, leukopenia, marked shortening of the villus, crypts of partial necrosis, increase im MPO activity, increased concentrations of IL-1  and changes in gastrointestinal motility. Treatment with dexamethasone, but not with metoclopramide, significantly reduced the intestinal lesions, with recovery of villous height, crypt depth, decreased MPO activity, reduced concentrations of IL-1. In addition, dexamethasone, but not metoclopramide, was able to reverse the delay in gastric emptying and increase in intestinal transit. Conclusion: The intestinal mucositis induced by irinotecan was able to cause gastrointestinal dismotility and inflammatory response with the participation of KC and IL1 which is associated with delay gastric emptying and gastrointestinal transit and acceleration of intestinal transit. It is also concluded that dexamethasone, but not metoclopramide, reduced the inflammatory response and modulated in part the gastrointestinal dismotility associated with irinotecan-induced intestinal mucositis.