Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

作者：Araujo C V; Lazzarotto C R; Aquino C C; Figueiredo I L; Costa T B; de Oliveira Alves L A; Ribeiro R A; Bertolini L R; Lima A A M; Brito G A C; Oria R B^*

来源：Brazilian Journal of Medical and Biological Research, 2015, 48(6): 493-501.

DOI：10.1590/1414-431X20144360

• Apolipoprotein E
• 5-Fluorouracil
• Alanyl-glutamine
• mucositis
• mice

Apolipoprotein E (APOE= gene, apoE= protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE(-/-)) and wild-type (APOE(+/+)) C57BL6J male and female mice (N= 86) were given either AlaGln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulinlike growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FUchallenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE(-/-) mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE(+/+) mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE(-/-)-challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

• 出版日期2015-6