Avaliação da resposta do hospedeiro murino frente à infecção pela bactéria oportunista pseudomonas aeruginosa em modelo de mucosite induzida pelo quimioterápico 5-fluorouracil (5-FU)

Abstract

Treatment of malignant tumors involves the use of chemotherapy in an attempt to control or combat disordered cell growth. However, several adverse effects occur during this treatment, such as severe inflammation of the mucosa of the gastrointestinal tract, known as gastrointestinal mucositis, as well as opportunistic infections with life-threatening complications. This study aimed to evaluate the host response to infection by opportunistic bacteria Pseudomonas aeruginosa in a model of mucositis induced by 5-Fluorouracil(5-Fu) chemotherapy. For this, four experimental groups consisting of Balb/c mice were used: G1 - PBS/Uninfected(saline-phosphate buffer); G2 - PBS/Infected; G3 - 5-Fu/Uninfected; G4 - 5-Fu/ Infected. Animals received an intraperitoneal dose of sterile saline or 5-Fu for 3 consecutive days for mucositis induction. The administration of 5-Fu chemotherapy resulted in the animals losing weight during three consecutive days of treatment, and moderately moist feces from the third day when compared to animals that were not treated with 5-Fu. Animal fecal DNA was extracted for analysis of bacterial phylogenetic groups. Faecal microbiota composition of animals under mucositis conditions was altered. Animals from the PBS/Infected and 5-Fu/Infected groups were infected intratracheally by the P. aeruginosa virulent strain PA14. Ten hours after infection, a greater recovery of viable bacteria in the lung, liver and spleen was observed in animals under mucositis conditions. Histopathological and stereological analysis showed that animals treated with 5-Fu presented structural lesions in the caecum. In the lung of the 5-Fu/non-infected group, the animals presented slight septal thickening but in the PBS/Infected and 5-Fu/Infected groups there was intense inflammatory infiltrate and alveolar septa thickening. The liver of infected animals showed intense inflammatory infiltrate with hydropic degeneration in hepatocytes. In the 5-Fu / uninfected group, these changes appear discreetly. Total lung and spleen RNA were extracted for analysis of differential expression of TNF-α(Tumor necrosis factor alpha) and iNOS(Nitric oxide synthase). Higher expression of TNF- a and iNOS genes was observed in the spleen of infected animals under mucositis conditions. iNOS expression was increased in the lungs of the 5-Fu/Infected group. The results suggest that administration of 5-Fu chemotherapy in a murine model makes it more susceptible to lung infection by opportunistic bacteria P. aeruginosa.