Prophylactic systemic P2X7 receptor blockade prevents experimental colitis
Prophylactic systemic P2X7 receptor blockade prevents experimental colitis
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DOI：
10.1016/j.bbadis.2013.10.012
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发表时间：
2014-01-01
影响因子：
6.2
通讯作者：
de Souza, Heitor S. P.
中科院分区：
文献类型：
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作者：
Marques, Carla Caldas;Castelo-Branco, Morgana T.;de Souza, Heitor S. P.
背景资料：P2 X7受体（P2 X7-R）是存在于上皮细胞和免疫细胞中的非选择性三磷酸腺苷门控阳离子通道，并参与炎症反应。在细胞应激或炎症条件下释放的细胞外核苷酸可以作为警告免疫系统炎症的危险信号。我们研究了P2 X7-R阻断在炎症性肠病模型中的治疗作用。研究方法：在诱导结肠炎之前，通过腹膜内（IP）或结肠内（IC）注射P2 X7-R拮抗剂A740003或亮蓝G（BBG）治疗患有三硝基苯磺酸（TNBS）诱导的结肠炎的大鼠。对临床和内镜随访、组织学评分、髓过氧化物酶活性、胶原纤维和杯状细胞密度进行评价。用免疫过氧化物酶法检测P2 X7-R表达、NF-κ B和Erk活性以及T细胞和巨噬细胞密度。通过酶联免疫吸附测定法测量结肠外植体培养物中的炎性细胞因子来确定炎症反应。TUNEL法检测结肠细胞凋亡。结果如下：IP-BBG显著减弱结肠炎的严重程度、髓过氧化物酶活性、胶原沉积、固有层T细胞和巨噬细胞的密度，同时维持杯状细胞密度。JP-BBG抑制P2 X7-R表达的增加与凋亡率平行。TNF-a和IL-113稳定在低水平，而TGF-13和IL-10在IPBG治疗后没有变化。结肠NF-κ-B和Erk活化在IP-BBG处理的动物中显著较低。预防性IP-A740003还保护大鼠免于发生TNBS-结肠炎。结论：预防性全身P2 X7-R阻断可有效预防实验性结肠炎，这可能是由于全身抗炎作用，干扰了P2 X7-R介导的应激-炎症放大环。(C)2013爱思唯尔有限公司版权所有。
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. JP-BBG inhibited the increase in P2X7-R expression in parallel with apoptotic rates. TNF-cc and interleuldn-113 stabilized in low levels, while TGF-I3 and interleukin-10 did not change following IPBBG-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. (C) 2013 Elsevier B.V. All rights reserved.