Effect of novel A2A adenosine receptor agonist ATL 313 on Clostridium difficile toxin A-induced murine ileal enteritis
Effect of novel A2A adenosine receptor agonist ATL 313 on Clostridium difficile toxin A-induced murine ileal enteritis
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DOI：
10.1128/iai.74.5.2606-2612.2006
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发表时间：
2006-05-01
影响因子：
3.1
通讯作者：
Brito, GAC
中科院分区：
文献类型：
--
作者：
Cavalcante, IC;Castro, MV;Brito, GAC
艰难梭菌是一种芽胞形成、厌氧、革兰氏阳性杆菌，它释放两种主要的毒力因子：毒素A和毒素B。毒素A在抗生素引起的腹泻和伪膜性结肠炎中起着重要的致病作用，伪膜性结肠炎是一种以强烈的粘膜炎症和分泌为特征的疾病。A(2A)腺苷受体的激动剂活性可减轻许多组织中的炎症和损伤。本研究观察了新型选择性A(2A)腺苷受体激动剂(ATL313)对毒素A诱导的小鼠回肠损伤的影响。在A毒素(1~10微克/环)或磷酸盐缓冲液(PBS)攻击前，立即将AT1313(0.5~5 NM)和/或A(2A)腺苷受体拮抗剂(ZM241385；5 NM)或磷酸盐缓冲盐水(PBS)注入回肠。3h后计算肠液体积/长度和重量/长度比。用末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记法(TUNEL)检测髓过氧化物酶、腺苷脱氨酶活性、肿瘤坏死因子-α(TNT-a)产生、组织病理学和细胞死亡情况。毒素A以剂量依赖的方式显著增加体积/长度和重量/长度比。AT1313治疗显著减少毒素A诱导的分泌和水肿，防止粘膜破坏，并通过髓过氧化物酶活性检测中性粒细胞的浸润。AT1313还可降低A毒素诱导的肿瘤坏死因子-α的产生和腺苷脱氨酶活性，并阻止A毒素诱导的细胞死亡。ATL 313的上述保护作用可被ZM241385逆转。总而言之，A(2A)腺苷受体激动剂ATL 313可以减轻A毒素引起的肠炎小鼠的组织损伤和炎症。给予A毒素后回肠腺苷脱氨酶活性升高的发现是新的，这可能通过脱氨内源性腺苷参与了A毒素诱导的肠炎的发病机制。
Clostridium difficile is a spore-forming, anaerobic, gram-positive bacillus that releases two main virulence factors: toxins A and B. Toxin A plays an important pathogenic role in antibiotic-induced diarrhea and pseudomembranous colitis, a condition characterized by intense mucosal inflammation and secretion. Agonist activity at A(2A) adenosine receptors attenuates inflammation and damage in many tissues. This study evaluated the effects of a new selective A(2A) adenosine receptor agonist (ATL 313) on toxin A-induced injury in murine ileal loops. ATL 313 (0.5 to 5 nM) and/or the A(2A) adenosine receptor antagonist (ZM241385; 5 nM) or phosphate-buffered saline (PBS) were injected into ileal loops immediately prior to challenge with toxin A (I to 10 mu g/loop) or PBS. Intestinal fluid volume/length and weight/length ratios were calculated 3 h later. heal tissues were collected for the measurement of myeloperoxidase, adenosine deaminase activity, tumor necrosis factor alpha (TNT-a) production, histopathology, and detection of cell death by the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) method. Toxin A significantly increased volume/length and weight/length ratios in a dose-dependent fashion. ATL 313 treatment significantly (P < 0.05) reduced toxin A-induced secretion and edema, prevented mucosal disruption, and neutrophil infiltration as measured by myeloperoxidase activity. ATL 313 also reduced the toxin A-induced TNF-alpha production and adenosine deaminase activity and prevented toxin A-induced cell death. These protective effects of ATL 313 were reversed by ZM241385. In conclusion, the A(2A) adenosine receptor agonist, ATL 313, reduces tissue injury and inflammation in mice with toxin A-induced enteritis. The finding of increased ileal adenosine deaminase activity following the administration of toxin A is new and might contribute to the pathogenesis of the toxin A-induced enteritis by deaminating endogenous adenosine.