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

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Abstract

Objective and design

This study attempted to clarify the roles of endothelins and mechanisms associated with ETA/ETB 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 (ETA receptor antagonist, 10 mg/kg), A-192621 (ETB 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. ETA and ETB 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 ETA receptors might be a potential target for inflammatory bowel diseases.

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Acknowledgements

The kind donations of Atrasentan and A-192621 by Dr. Terry Opgenorth (Abbott Laboratories, Abbott Park, USA) is gratefully acknowledged. The study was supported by the Brazilian National Research Council (CNPq), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Capes) and Fundacao de Amparo a Ciencia e Tecnologia do Estado de Santa Catarina (Funcitec).

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Authors and Affiliations

  1. Department of Pharmacology, Biological Sciences Center, Federal University of Santa Catarina, Florianopolis, SC, Brazil

    R. F. Claudino, D. F. Leite, A. F. Bento, J. B. Calixto & G. A. Rae

  2. Department of Pharmacology, Biological Sciences Center, Federal University of Parana, Curitiba, PR, 81531-980, Brazil

    R. F. Claudino & J. G. Chichorro

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  1. R. F. Claudino
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  2. D. F. Leite
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  5. J. B. Calixto
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Correspondence to R. F. Claudino.

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Claudino, R.F., Leite, D.F., Bento, A.F. et al. Potential role for ET-2 acting through ETA receptors in experimental colitis in mice. Inflamm. Res. 66, 141–155 (2017). https://doi.org/10.1007/s00011-016-1001-7

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