Efeitos da imunomodulação em animais sobreviventes de Sepse grave sobre as alterações inflamatórias observadas na mucosite intestinal induzida por irinotecano

Abstract

Nowadays the colorectal cancer (CRC) is one of the most common malignant tumors. Irinotecan have been used in the treatment of CRC and metastatic CRC. However, the treatment protocols are associated with the development of intestinal mucositis (IM), reaction that affects the therapy. The IM and severe diarrhea are common side effects that may reach 15-25% of the patients undergoing chemotherapy and the clinical management of these effects is still partly ineffective. The study of the mechanisms and mediators involved in immune response in post-sepsis has provided evidences that in this condition seems to be an inhibition of inflammatory events including neutrophil migration. Thus, the post-sepsis could influence the course of MI induced by IRI. The aim of this study is to evaluate the effects of immunomodulation in the development of inflammatory changes of IM induced by Irinotecan in severe sepsis surviving animals. C57BL / 6 male mice, 20-25g, were divided into 4 groups (n = 5-8) were subjected to the model of cecal ligation and puncture (CLP) and treated with ertapenem 20mg/kg i.p. 6 h after CLP and 12/12h for three days to induce approximately 50% of survival. Animals underwent surgery but not to puncture the cecum (SHAM) received saline (NaCl, 5 mL / kg, ip). Fifteen days after CLP, the surviving animals and animals of the SHAM group received saline (NaCl, 5 ml / kg, ip) for 4 days or Irinotecan (75mg/kg, ip). The body mass (g) was measured every day. On the 5th or 7th day, total leukocyte count (x103/μL) and diarrhea (scores) were evaluated. After the death, the jejunum and the ileum were collected for determination of myeloperoxidase (MPO), IL-1β and IL-10 (pg / ml) and histopathological analysis. ANOVA / Kruskal Wallis test or Bonferroni / Dunn were used as statistical tests. P <0.05 was accepted. CEPA 84/2014 protocol. Post-septic animal by CLP treated with Irinotecan decreased scores of diarrhea and MPO activity in the 5th and 7th day (diarrhea 5D: [0 (0-0)]; 7D: [0 (0-2) / MPO jejunum and ileum 5D: 2.96 ± 1.08, 2.35 ± 0.76 and 7D: 0.42 ± 0.14, 0.92 ± 0.19, respectively) compared against the SHAM animals treated with Irinotecan (diarrhea 5D: [1(0-1)]; 7D: [2.5 (1-3)] / MPO jejunum and ileum 5D: 8.15 ± 1.48, 7.96 ± 0.96; 7D: 2.51 ± 0.67, 2.87 ± 0.65, respectively). Furthermore, post-septic mice treated with Irinotecan decreased histopathological damage in the 5th and 7th day (5D jejunum and ileum: [1(1-3)] and [1(0-1)], and 7D in the ileum: [2 (1-3)] for Irinotecan (jejunum and ileum 5D: [4 (2-4)] and [4 (1-4)] / 7D: ileum [4 (3-4)]) and increased levels of IL-10 (jejunum and ileum 5D: 55.80 ± 3.42; 34.45 ± 1.87; 7D: Ileum: 133.00 ± 20.25) compared against the SHAM + IRI (5D in jejunum and ileum: 34.45 ± 1.87; 6.91 ± 3.05; 7D ileum:. 63.67 ± 9.08). However, IRI + CLP animals had no change of IRI-induced leukopenia. C57BL/6 post-septic animals had reduced intestinal mucosal injury and neutrophil infiltration in IM induced by Irinotecan, this effect can be consequential, among others, of the increase in IL-10.