Influência do gene Ahr no desenvolvimento da Colite Ulcerativa por sulfato sódico de dextrana em modelo animal de inflamação aguda

Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by a chronic process that causes lesions in the colon mucosa and is correlated with an increased risk of intestinal carcinogenesis. The development of UC involves environmental and genetic factors being known as a multifactorial disease. Genetic studies have indicated an association between variants of the Ahr (aromatic hydrocarbon receptor) gene and UC disease, since the AHR protein plays an important role in the progression of the disease. The most efficient experimental model of UC was performed by ingestion of sodium dextran sulfate (DSS) by animals susceptible to inflammation. Mice genetically selected for high (AIRmax) or low (AIRmin) acute inflammatory response (AIR) for Biogel subcutaneous injection were used as a experimental model to study the involvement of AHR in UC evolution. During the AIR selection process, the Ahrd (low affinity) and Ahrb1 (high affinity) alleles were fixed in AIRmax and AIRmin mice, respectively. As the Ahr genetic polymorphism is associated with the low and high affinity of the AHR, our objective was to study the relationship between the intensity of UC produced by DSS ingestion and the Ahr polymorphism in mice phenotypically selected for AIR. The AIRmax and AIRmin mice and Balb/c and C57Bl/6 isogenic strains were separated into groups and treated with 0, 2, 2.5 or 3% DSS (30-50 kDa - MP) diluted in distilled water for 7 consecutive days. To verify UC modulation, groups of AIRmax and AIRmin mice were treated with DSS associated to α-naphthoflavone an AHR antagonist dissolved in olive oil and orally administered by gavage for 7 consecutive days. The parameters considered for characterization of UC were weight loss, diarrhea and bloody stools as disease activity index (IAD) and myeloperoxidase activity measure and histopathological analysis. Our data show that the 3% dose of DSS induces UC mainly in AIRmax, Balb / c and C57Bl / 6 mice characterized by IAD. Seven days (acute) and 30 (chronic) days after the start of DSS treatment, colon size, MPO activity and histological architecture were the best parameters associated with IAD. In different degrees, a decrease of the IAD in the AIRmin mice was observed. Therefore, AHR is considered an important ulcerative colitis modulator.