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腺苷 A₂A 受体激动剂和丙氨酰-谷氨酰胺对艰难梭菌毒素诱导的兔回肠炎和小鼠盲肠炎的作用。

Effects of adenosine A₂A receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice.

机构信息

Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.

出版信息

BMC Infect Dis. 2012 Jan 20;12:13. doi: 10.1186/1471-2334-12-13.

DOI:10.1186/1471-2334-12-13
PMID:22264229
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3323464/
Abstract

BACKGROUND

Severe Clostridium difficile toxin-induced enteritis is characterized by exuberant intestinal tissue inflammation, epithelial disruption and diarrhea. Adenosine, through its action on the adenosine A2A receptor, prevents neutrophillic adhesion and oxidative burst and inhibits inflammatory cytokine production. Alanyl-glutamine enhances intestinal mucosal repair and decreases apoptosis of enterocytes. This study investigates the protection from enteritis by combination therapy with ATL 370, an adenosine A2A receptor agonist, and alanyl-glutamine in a rabbit and murine intestinal loop models of C. difficile toxin A-induced epithelial injury.

METHODS

Toxin A with or without alanyl-glutamine was administered intraluminally to rabbit ileal or murine cecal loops. Animals were also given either PBS or ATL 370 parenterally. Ileal tissues were examined for secretion, histopathology, apoptosis, Cxcl1/KC and IL-10.

RESULTS

ATL 370 decreased ileal secretion and histopathologic changes in loops treated with Toxin A. These effects were reversed by the A2A receptor antagonist, SCH 58261, in a dose-dependent manner. The combination of ATL 370 and alanyl-glutamine significantly further decreased ileal secretion, mucosal injury and apoptosis more than loops treated with either drug alone. ATL 370 and alanyl-glutamine also decreased intestinal tissue KC and IL-10.

CONCLUSIONS

Combination therapy with an adenosine A2A receptor agonist and alanyl-glutamine is effective in reversing C. difficile toxin A-induced epithelial injury, inflammation, secretion and apoptosis in animals and has therapeutic potential for the management of C. difficile infection.

摘要

背景

严重的艰难梭菌毒素诱导性肠炎的特征是肠组织炎症旺盛、上皮破坏和腹泻。腺苷通过其对腺苷 A2A 受体的作用，可防止中性粒细胞黏附和氧化爆发，并抑制炎症细胞因子的产生。丙氨酰-谷氨酰胺可增强肠黏膜修复，减少肠上皮细胞凋亡。本研究在艰难梭菌毒素 A 诱导的上皮损伤的兔和鼠肠袢模型中，通过合用腺苷 A2A 受体激动剂 ATL 370 和丙氨酰-谷氨酰胺来研究对肠炎的保护作用。

方法

毒素 A 与或不与丙氨酰-谷氨酰胺经腔内给予兔回肠或鼠盲肠袢。动物也接受 PBS 或 ATL 370 肠外给药。检测回肠组织的分泌、组织病理学、凋亡、Cxcl1/KC 和 IL-10。

结果

ATL 370 降低了毒素 A 处理的肠袢的分泌和组织病理学变化。这些作用可被 A2A 受体拮抗剂 SCH 58261 以剂量依赖的方式逆转。ATL 370 与丙氨酰-谷氨酰胺联合应用显著进一步降低了回肠分泌、黏膜损伤和凋亡，比单独使用任一药物的肠袢更为明显。ATL 370 和丙氨酰-谷氨酰胺还降低了肠组织 KC 和 IL-10。

结论

合用腺苷 A2A 受体激动剂和丙氨酰-谷氨酰胺可有效逆转艰难梭菌毒素 A 诱导的动物上皮损伤、炎症、分泌和凋亡，对艰难梭菌感染的治疗具有潜在作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/cc6eb3c40afb/1471-2334-12-13-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/3bcd10f414d7/1471-2334-12-13-1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/7095a26a81a3/1471-2334-12-13-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/aebd03a3dedd/1471-2334-12-13-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/a68199513877/1471-2334-12-13-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/cc6eb3c40afb/1471-2334-12-13-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/3bcd10f414d7/1471-2334-12-13-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/c5588c5403cc/1471-2334-12-13-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/7095a26a81a3/1471-2334-12-13-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/aebd03a3dedd/1471-2334-12-13-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/a68199513877/1471-2334-12-13-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31b7/3323464/cc6eb3c40afb/1471-2334-12-13-6.jpg

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