Prophylactic systemic P2X7 receptor blockade prevents experimental colitis
| Autor: | Carla Marques, Alberto Schanaider, Heitor Siffert Pereira de Souza, Rodrigo G. Pacheco, Fernanda Buongusto, Morgana T. Castelo-Branco, Alyson do Rosario, Robson Coutinho-Silva |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Purinergic P2X Receptor Antagonists Colon T-Lymphocytes Anti-Inflammatory Agents Gene Expression Inflammation Apoptosis Pharmacology P2X7-R Inflammatory bowel disease Proinflammatory cytokine Immune system P2X7-R blockade Internal medicine medicine Rosaniline Dyes Animals Colitis Rats Wistar Extracellular Signal-Regulated MAP Kinases Molecular Biology Peroxidase Brilliant blue G Innate immunity Goblet cell Innate immune system TUNEL assay Chemistry Macrophages NF-kappa B medicine.disease Rats medicine.anatomical_structure Endocrinology Trinitrobenzenesulfonic Acid TNBS-induced colitis Molecular Medicine Collagen Goblet Cells Receptors Purinergic P2X7 medicine.symptom Injections Intraperitoneal |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842(1):65-78 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2013.10.012 |
| Popis: | Background The P2X7 receptor (P2X7-R) is a non-selective adenosine triphosphate-gated cation channel present in epithelial and immune cells, and involved in inflammatory response. Extracellular nucleotides released in conditions of cell stress or inflammation may function as a danger signal alerting the immune system from inflammation. We investigated the therapeutic action of P2X7-R blockade in a model of inflammatory bowel disease. Methods Rats with trinitrobenzene sulfonic (TNBS) acid-induced colitis were treated with the P2X7-R antagonists A740003 or brilliant blue G (BBG) through intra-peritoneal (IP) or intra-colonic (IC) injection prior to colitis induction. Clinical and endoscopic follow-up, histological scores, myeloperoxidase activity, densities of collagen fibers and goblet cells were evaluated. P2X7-R expression, NF-kappa B and Erk activities, and densities of T-cells and macrophages were analyzed by immunoperoxidase. The inflammatory response was determined by measuring inflammatory cytokines in cultures of colon explants, by enzyme-linked immunosorbent assay. Colonic apoptosis was determined by the TUNEL assay. Results IP-BBG significantly attenuated the severity of colitis, myeloperoxidase activity, collagen deposition, densities of lamina propria T-cells and macrophages, while maintaining goblet cell densities. IP-BBG inhibited the increase in P2X7-R expression in parallel with apoptotic rates. TNF-α and interleukin-1β stabilized in low levels, while TGF-β and interleukin-10 did not change following IP-BBG-therapy. Colonic NF-kappa-B and Erk activation were significantly lower in IP-BBG-treated animals. Prophylactic IP-A740003 also protected rats against the development of TNBS-colitis. Conclusions Prophylactic systemic P2X7-R blockade is effective in the prevention of experimental colitis, probably due to a systemic anti-inflammatory action, interfering with a stress-inflammation amplification loop mediated by P2X7-R. |
| Databáze: | OpenAIRE |
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