Efeito da pentoxifilina e da dexametasona na resposta inflamatória e nas alterações da motilidade digestiva associadas à mucosite intestinal induzida por 5- fluorouracil em ratos

Abstract

One of the most important limitation of antineoplasic chemotherapy is the intestinal mucositis. Mucositis is a clinical term wich describes a syndrome characterized for ulceration in the digestive tract. Gastrointestinal tract is vulnerable because it have elevated proliferation cellular renovation. Intestinal mucositis results in inflammatory events, that leads the alterations in permeability and gastrointestinal motility in the inflammatory phase, as in the post-inflammatory phase. Pentoxifylline (PTX) is important inhibitor of the cytokines synthesis, with a protective effect against 5-FU- induced oral mucositis in hamster. Dexamethasone (DEXA) is glucorticoide with anti-inflammatory and immunosuppressive effects. Aim: To evaluate the effect of the pentoxifylline or dexamethasone treatments in the inflammatory response and alterations of the gastrointestinal motility associate with 5-FU- induced intestinal mucositis. Methods: Male Wistar rats (200 – 250g) treated in d0 by 5-FU (150 mg/Kg, i.p. only dose) or 5-FU + PTX (90 mg/Kg, s.c.) or 5-FU + DEXA (2.5mg/Kg, i.p.). PTX or DEXA were administrated 30’ after 5-FU, and then daily. In d3, animals were sacrificed, samples duodenum, jejunum and ileum were removed for assessment epithelial damage for morphometric, histological scores, MPO activity and GSH concentration. In order to evaluate the concentration of TNF- and IL-1, duodenum samples were removed and ELISA or imunohistoquimic for this cytocines were performed. In order to evaluated the gastrointestinal motility, animals received same treatment described previously, then were fasted for 18h of the d2 to d3. In d3 the animals were gavage-fed with a test meal and sacrificed 20 min later. Stomach and consecutive intestinal segments same (proximal, medial and distal) were obtained. Each segment was placed in a measuring cylinder and the volume measured by adding 100 mL of 0.1 NaOH. The absorbance of the sample was read at a 540 nm. Results: The treatment with 5-FU induced intestinal damage with an important disruption of the functional epithelial barrier and presence of these following alterations: shortening villus, partial necrosis crypts, vacuolated cells, presence of infiltrated mono and polymorphonuclears, production of free radicals with GSH consumption, increase in the concentration of TNF- and IL-1 in the duodenum, and gastrointestinal dismotility. The treatment with DEXA and PTX significantly reduced the intestinal damage, with recovery of the high villus, depth of crypt, reduction of the neutrophil infiltration, increase of the levels of glutathione and reduction in the TNF- and IL-1 concentrations. However, only the treatment with DEXA was able to reverse the delays gastric emptying and gastrointestinal transit induced by intestinal mucositis. Conclusion: 5-FU induces intestinal mucositis in rats with the participation of TNF- and IL-1. It associates with delayed gastric emptying and gastrointestinal transit. We conclude also that PTX or DEXA- treatments decreases the inflammatory response. On the other hand, only DEXA treatment reversed gastrointestinal dismotility associate with 5– FU- induced intestinal mucositis in rats.