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

• Published in: Inflammation research Vol. 66; no. 2; pp. 141 - 155
• Main Authors: Claudino, R. F., Leite, D. F., Bento, A. F., Chichorro, J. G., Calixto, J. B., Rae, G. A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2017; Springer Nature B.V
• Subjects: Allergology; Animals; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; Colitis - pathology; Colon - drug effects; Colon - immunology; Colon - pathology; Cytokines - immunology; Dermatology; Dextran Sulfate; E-Selectin - immunology; Endothelin A Receptor Antagonists - pharmacology; Endothelin A Receptor Antagonists - therapeutic use; Endothelin B Receptor Antagonists - pharmacology; Endothelin-1 - genetics; Endothelin-1 - immunology; Endothelin-2 - genetics; Endothelin-2 - immunology; Immunology; Leukocytes - drug effects; Leukocytes - immunology; Male; Mice, Inbred BALB C; Neurology; Neutrophil Infiltration - drug effects; Original Research Paper; P-Selectin - immunology; Peroxidase - immunology; Pharmacology/Toxicology; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Receptor, Endothelin A - genetics; Receptor, Endothelin A - immunology; Receptor, Endothelin B - genetics; Receptor, Endothelin B - immunology; Rheumatology; RNA, Messenger - metabolism; Trinitrobenzenesulfonic Acid; Endothelins; Colitis; 2,4,6-Trinitrobenzene sulfonic acid; Dextran sulfate sodium
• ISSN: 1023-3830; 1420-908X
• DOI: 10.1007/s00011-016-1001-7

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.