Prophylactic systemic P2X7 receptor blockade prevents experimental colitis
Open accessAbstract
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.
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P2rx7−/− mice were protected against experimental induction of colitis, as were rats treated prophylactically with a chemical P2X7 antagonist.
“P2rx7−/− mice were protected against experimental induction of colitis, as were rats treated prophylactically with a chemical P2X7 antagonist (Marques et al., 2014; Neves et al., 2014).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Marques et al., 2014
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References 83 · Cited by 78
- Authors
- Marques, C. C., Castelo-Branco, M. T., Pacheco, R. G., Buongusto, F., do Rosário, A., Schanaider, A., Coutinho-Silva, R., & de Souza, H. S. P.
- Affiliations
- Universidade Federal do Rio de Janeiro (BR)
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 1842
- Issue
- 1
- Pages
- 65-78
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2022548397
- Cited by
- 78
- References
- 83
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 10 · 2021: 4 · 2020: 2 · 2019: 7 · 2018: 7 · 2017: 14 · 2016: 4 · 2015: 4 · 2014: 5
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brazilian Research Council (CNPq)
- FAPERJ (Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- P2X7 receptor, inflammatory bowel disease, experimental colitis, TNBS-induced colitis, Brilliant Blue G, P2X7 receptor antagonists, prophylaxis, NF-κB, ERK signaling, myeloperoxidase, lamina propria T cells, macrophages, goblet cells, TNF-α, IL-1β, extracellular nucleotides, anti-inflammatory therapy
- MeSH terms
- Animals, Anti-Inflammatory Agents, Colitis, Collagen, Colon, Injections, Intraperitoneal, Macrophages, Male, Peroxidase, Rosaniline Dyes, T-Lymphocytes, Trinitrobenzenesulfonic Acid, Gene Expression, NF-kappa B, Rats, Wistar, Apoptosis, Goblet Cells, Extracellular Signal-Regulated MAP Kinases, Rats, Receptors, Purinergic P2X7, Purinergic P2X Receptor Antagonists
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