Efeito da pentamidina na modulação da inflamação, do estresse oxidativo e nas alterações histológicas na mucosite induzida por 5-fluorouracil

Abstract

5-fluorouracil (5-FU) is widely used in the treatment of breast and colorectal cancer. After the first dose of 5-FU, 40% of the patients can exhibite intestinal mucositis that may be accompanied by diarrhea. 5-FU-induced intestinal mucositis may have an important relation with alterations in Enteric glial cells, since these cells are involved in the interaction with both neurons and epithelial cells. Enteric glial cells synthesize S100ꞵ, which is considered a proinflammatory cytokine because of its ability to promote inflammation, enhancing the gene expression of iNOS, IL-6 and TNF-α via S100ꞵ-RAGE-NFκB. Therefore, this study aimed to investigate the effect of pentamidine, a S100ꞵ inhibitor, on the 5-FU-induced intestinal mucositis. Male Swiss mice received saline (0.9%, i.p.) or 5-FU (450 mg / kg, i.p. single dose). After 24 hours of chemotherapeutic administration, pentamidine (P0.8 mg / kg + 5FU, P4 mg / kg + 5FU, or only P4mg / kg, ip) was injected for two days and the animals were euthanized in the fourth day of the experimental protocol. The animals were monitored daily to analyze the weight loss. The segments of the small intestine and colon were collected for analysis of the following parameters: histopathological aspects (identifying histopathological changes and measuring villus height, including intestinal crypt length), oxidative stress (by measuring the levels of GSH-reduced glutathione - and malondialdehyde-MDA) and inflammation (measuring levels of nitrite and nitrate-NOx- and proinflammatory cytokines TNF-α and IL-6) in the intestinal samples. 5-FU promoted significant weight loss, reduced villus height and intestinal crypt length, including intense infiltrate of inflammatory cells. In addition, 5-FU increased the levels of MDA, NOx, TNF-α and IL-6, as well as reduced GSH levels in the intestine when compared to the control group. Whereas Pentamidine (a S100ꞵ inhibitor) reduced these 5-FU promoted changes in the gut. Based on the findings, S100ꞵ is an important mediator on the pathogenesis of the 5-FU-induced intestinal mucositis, since its inhibition attenuates weight loss, histological changes, oxidative stress and inflammation induced by this chemotherapeutic agent. Therefore, S100ꞵ is shown to be an important target molecule for the development of future therapies to attenuate 5-FU-induced damage on the intestinal mucosa.