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 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.

• Authors: R F Claudino, D F Leite, A F Bento, J G Chichorro, J B Calixto, G A Rae
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 66 Issue 2 Pg. 141-155 (Feb 2017) ISSN: 1420-908X [Electronic] Switzerland
• PMID: 27778057 (Publication Type: Journal Article)

Chemical References

• A 192621
• Cytokines
• E-Selectin
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1
• Endothelin-2
• P-Selectin
• Pyrrolidines
• RNA, Messenger
• Receptor, Endothelin A
• Receptor, Endothelin B
• Trinitrobenzenesulfonic Acid
• Dextran Sulfate
• Peroxidase
• Atrasentan

Topics

• Animals
• Atrasentan
• Cells, Cultured
• Colitis (chemically induced, drug therapy, immunology, pathology)
• Colon (drug effects, immunology, pathology)
• Cytokines (immunology)
• Dextran Sulfate
• E-Selectin (immunology)
• Endothelin A Receptor Antagonists (pharmacology, therapeutic use)
• Endothelin B Receptor Antagonists (pharmacology)
• Endothelin-1 (genetics, immunology)
• Endothelin-2 (genetics, immunology)
• Leukocytes (drug effects, immunology)
• Male
• Mice, Inbred BALB C
• Neutrophil Infiltration (drug effects)
• P-Selectin (immunology)
• Peroxidase (immunology)
• Pyrrolidines (pharmacology, therapeutic use)
• RNA, Messenger (metabolism)
• Receptor, Endothelin A (genetics, immunology)
• Receptor, Endothelin B (genetics, immunology)
• Trinitrobenzenesulfonic Acid