Prophylactic systemic P2X7 receptor blockade prevents experimental colitis.
Biochim Biophys Acta
; 1842(1): 65-78, 2014 Jan.
Article
em En
| MEDLINE
| ID: mdl-24184714
ABSTRACT
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-1ß stabilized in low levels, while TGF-ß 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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Corantes de Rosanilina
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Colite
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Colo
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Receptores Purinérgicos P2X7
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Antagonistas do Receptor Purinérgico P2X
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Anti-Inflamatórios
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article