Contribution of adenosine A(2B) receptors in Clostridium difficile intoxication and infection.
Contribution of adenosine A(2B) receptors in Clostridium difficile intoxication and infection.
复制标题
腺苷 A(2B) 受体在艰难梭菌中毒和感染中的作用。
DOI：
10.1128/iai.00782-12
复制
发表时间：
2012
影响因子：
3.1
通讯作者：
Guerrant,RichardL
中科院分区：
文献类型：
--
作者：
Warren,CirleA;Li,Yuesheng;Calabrese,GinaM;Freire,RosemayreS;Zaja-Milatovic,Snjezana;vanOpstal,Edward;Figler,RobertA;Linden,Joel;Guerrant,RichardL
艰难梭菌毒素 A (TcdA) 和 B (TcdB) 可诱导明显的全身和肠道炎症反应。 A2腺苷受体 (A2BAR) 是肠上皮细胞中主要的腺苷受体。我们研究了 TcdA 或 TcdB 是否上调人类肠道细胞中的 A2BAR，以及阻断 A2BAR 是否可以改善艰难梭菌 TcdA 诱导的肠炎并改变艰难梭菌感染 (CDI) 的结果。在 HCT-8 细胞中检测腺苷受体亚型（A1、A2A、A2B 和 A3）mRNA。用 TcdA 处理来自野生型兔子和小鼠以及 A2BAR−/− 小鼠的回肠环，有或没有选择性 A2BAR 拮抗剂 ATL692 或 PSB1115。使用 CDI 小鼠模型来确定 A2BAR 缺失或口服药物 ATL801 阻断对临床结果、组织病理学和感染引起的肠道白细胞介素 6 (IL-6) 表达的影响。 TcdA 和 TcdB 上调 HCT-8 细胞中 A2BAR 基因的表达。 ATL692 减少兔回肠中 TcdA 诱导的分泌和上皮损伤。 A2BAR 的缺失减少了 TcdA 攻击小鼠回肠的分泌和组织病理学。删除或阻断 A2BAR 可减少艰难梭菌感染小鼠的组织病理学、IL-6 表达、体重减轻、腹泻和死亡率。 A2BAR 介导艰难梭菌毒素诱导的肠炎和疾病。抑制 A2BAR 激活可能是限制 CDI 发病率和死亡率的潜在策略。
Clostridium difficile toxins A (TcdA) and B (TcdB) induce a pronounced systemic and intestinal inflammatory response. A2Badenosine receptors (A2BARs) are the predominant adenosine receptors in the intestinal epithelium. We investigated whether A2BARs are upregulated in human intestinal cells by TcdA or TcdB and whether blockade of A2BARs can ameliorate C. difficile TcdA-induced enteritis and alter the outcome of C. difficile infection (CDI). Adenosine receptor subtype (A1, A2A, A2B, and A3) mRNAs were assayed in HCT-8 cells. Ileal loops from wild-type rabbits and mice and A2BAR−/−mice were treated with TcdA, with or without the selective A2BAR antagonist ATL692 or PSB1115. A murine model of CDI was used to determine the effect of A2BAR deletion or blockade with the orally available agent ATL801, on clinical outcome, histopathology and intestinal interleukin-6 (IL-6) expression from infection. TcdA and TcdB upregulated A2BAR gene expression in HCT-8 cells. ATL692 decreased TcdA-induced secretion and epithelial injury in rabbit ileum. Deletion of A2BARs reduced secretion and histopathology in TcdA-challenged mouse ileum. Deletion or blockade of A2BARs reduced histopathology, IL-6 expression, weight loss, diarrhea, and mortality in C. difficile-infected mice. A2BARs mediate C. difficile toxin-induced enteritis and disease. Inhibition of A2BAR activation may be a potential strategy to limit morbidity and mortality from CDI.