PGI2 Inhibits Intestinal Epithelial Permeability and Apoptosis to Alleviate Colitis.

Abstract

BACKGROUND & AIMS:

Inflammatory bowel diseases (IBDs) that encompass both ulcerative colitis and Crohn's disease are a major public health problem with an etiology that has not been fully elucidated. There is a need to improve disease outcomes and preventive measures by developing new effective and lasting treatments. Although polyunsaturated fatty acid metabolites play an important role in the pathogenesis of several disorders, their contribution to IBD is yet to be understood.

METHODS:

Polyunsaturated fatty acids metabolite profiles were established from biopsy samples obtained from Crohn's disease, ulcerative colitis, or control patients. The impact of a prostaglandin I2 (PGI2) analog on intestinal epithelial permeability was tested in vitro using Caco-2 cells and ex vivo using human or mouse explants. In addition, mice were treated with PGI2 to observe dextran sulfate sodium (DSS)-induced colitis. Tight junction protein expression, subcellular location, and apoptosis were measured in the different models by immunohistochemistry and Western blotting.

RESULTS:

A significant reduction of PGI2 in IBD patient biopsies was identified. PGI2 treatment reduced colonic inflammation, increased occludin expression, decreased caspase-3 cleavage and intestinal permeability, and prevented colitis development in DSS-induced mice. Using colonic explants from mouse and human control subjects, the staurosporine-induced increase in paracellular permeability was prevented by PGI2. PGI2 also induced the membrane location of occludin and reduced the permeability observed in colonic biopsies from IBD patients.

CONCLUSIONS:

The present study identified a PGI2 defect in the intestinal mucosa of IBD patients and demonstrated its protective role during colitis.

• Authors: Camille Pochard, Jacques Gonzales, Anne Bessard, Maxime M Mahe, Arnaud Bourreille, Nicolas Cenac, Anne Jarry, Emmanuel Coron, Juliette Podevin, Guillaume Meurette, Michel Neunlist, Malvyne Rolli-Derkinderen
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 12 Issue 3 Pg. 1037-1060 ( 2021) ISSN: 2352-345X [Electronic] United States
• PMID: 33971327 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Fatty Acids, Unsaturated
• Tight Junction Proteins
• Dextran Sulfate
• Epoprostenol

Topics

• Adult
• Aged
• Animals
• Caco-2 Cells
• Case-Control Studies
• Colitis (chemically induced, drug therapy, genetics, metabolism)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Epoprostenol (administration & dosage, pharmacology)
• Fatty Acids, Unsaturated (metabolism)
• Female
• Humans
• Inflammatory Bowel Diseases (chemically induced, drug therapy, metabolism, surgery)
• Intestinal Mucosa (cytology, drug effects, metabolism)
• Male
• Metabolomics
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Permeability (drug effects)
• Tight Junction Proteins (genetics)
• Young Adult