Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease
Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease
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DOI：
10.1053/j.gastro.2005.05.032
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发表时间：
2005-07-01
期刊：
影响因子：
29.4
通讯作者：
Cominelli, F
中科院分区：
文献类型：
--
作者：
Odashima, M;Bamias, G;Cominelli, F
背景和目的：腺苷被认为是炎症反应的重要调节剂。已描述了四种腺苷受体亚型（A(1)、A(2A)、A(2B) 和 A(3)），其中 A(2A) 可能抑制炎症。本研究的目的是通过向炎症性肠病实验模型施用选择性 A(2A) 激动剂 (ATL-146e) 来研究 A(2A) 在粘膜炎症中的作用。方法：在急性和慢性兔福尔马林免疫复合物结肠炎模型和SAMP1/YitFc小鼠自发性回肠炎模型中研究ATL-146e的抗炎作用。结果：在兔免疫性结肠炎急性模型中，与载体相比，ATL-146e 显着降低急性炎症指数和组织坏死（P < .01）。在慢性兔免疫性结肠炎模型中，ATL-146e 显着抑制炎症细胞浸润结肠粘膜 (P < .05) 并预防死亡。 ATL-146e 的给药显着降低了 SAMP1/YitFc 小鼠回肠的慢性炎症指数 (P < .01) 和绒毛扭曲指数 (P < .01)，并改善了注射 SAMP-1/yit 小鼠 CD4(+) T 细胞的严重联合免疫缺陷小鼠的过继转移性回肠炎 (P < .05)。在 SAMP1/YitFc 小鼠肠系膜淋巴结细胞培养物上清液中，ATL-146e 处理显着抑制肿瘤坏死因子、干扰素 γ 和白细胞介素 4 浓度（与媒介物处理小鼠相比，P < 0.05）。结论：ATIL-146e 激活 A(2A) 腺苷受体可显着减轻肠粘膜炎症。这种作用与白细胞浸润减少和促炎细胞因子抑制有关。因此，通过选择性激动激活 A(2A) 可能作为治疗炎症性肠病的新疗法。
Background & Aims: Adenosine has been implicated as an important regulator of the inflammatory response. Four subtypes of adenosine receptors (A(1), A(2A), A(2B), and A(3)) have been described, of which A(2A) potentially inhibits inflammation. The aim of this study was to investigate the role of A(2A) in mucosal inflammation by administering a selective A(2A) agonist (ATL-146e) to experimental models of inflammatory bowel disease. Methods: The anti-inflammatory effects of ATL-146e were studied in the acute and chronic rabbit formalin-immune complex models of colitis and the SAMP1/YitFc mouse model of spontaneous ileitis. Results: ATL-146e significantly reduced the acute inflammatory index and tissue necrosis compared with vehicle (P < .01) in the acute model of rabbit immune colitis. In the chronic rabbit immune colitis model, ATL-146e significantly suppressed inflammatory cell infiltration into the colonic mucosa (P < .05) and prevented mortality. The administration of ATL-146e significantly decreased the chronic inflammatory index (P < .01) and villus distortion index (P < .01) in the ileum of SAMP1/YitFc mice, and ameliorated adoptively transferred ileitis in severe combined immunodeficient mice injected with CD4(+) T cells from SAMP-1/yit mice (P < .05). Tumor necrosis factor, interferon gamma, and interleukin 4 concentrations were significantly suppressed by ATL-146e treatment in supernatants from cultures of mesenteric lymph node cells of SAMP1/YitFc mice (P < .05 vs vehicle-treated mice). Conclusions: A(2A) adenosine receptor activation by ATIL-146e significantly reduced inflammation in the intestinal mucosa. This effect was associated with decreased leukocyte infiltration and inhibition of proinflammatory cytokines. Activation of A(2A) by selective agonism may therefore serve as a novel therapy for the treatment of inflammatory bowel disease.