Potential role for ET-2 acting through ETA receptors in experimental colitis in mice

Abstract

Objective and design: This study attempted to clarify the roles of endothelins and mechanisms associated with ET_A/ET_B receptors in mouse models of colitis.

Materials and methods: Colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 1.5 mg/animal) or dextran sulfate sodium (DSS, 3%). After colitis establishment, mice received Atrasentan (ET_A receptor antagonist, 10 mg/kg), A-192621 (ET_B receptor antagonist, 20 mg/kg) or Dexamethasone (1 mg/kg) and several inflammatory parameters were assessed, as well as mRNA levels for ET-1, ET-2 and ET receptors.

Results: Atrasentan treatment ameliorates TNBS- and DSS-induced colitis. In the TNBS model was observed reduction in macroscopic and microscopic score, colon weight, neutrophil influx, IL-1β, MIP-2 and keratinocyte chemoattractant (KC) levels, inhibition of adhesion molecules expression and restoration of IL-10 levels. However, A192621 treatment did not modify any parameter. ET-1 and ET-2 mRNA was decreased 24 h, but ET-2 mRNA was markedly increased at 48 h after TNBS. ET-2 was able to potentiate LPS-induced KC production in vitro. ET_A and ET_B receptors mRNA were increased at 24, 48 and 72 h after colitis induction.

Conclusions: Atrasentan treatment was effective in reducing the severity of colitis in DSS- and TNBS-treated mice, suggesting that ET_A receptors might be a potential target for inflammatory bowel diseases.

Keywords: 2,4,6-Trinitrobenzene sulfonic acid; Colitis; Dextran sulfate sodium; Endothelins.