Cannabinoid CB2 receptor activation attenuates cytokine-evoked mucosal damage in a human colonic explant model without changing epithelial permeability
Cannabinoid CB2 receptor activation attenuates cytokine-evoked mucosal damage in a human colonic explant model without changing epithelial permeability
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DOI：
10.1016/j.cyto.2013.04.032
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发表时间：
2013-08-01
期刊：
影响因子：
3.8
通讯作者：
Smid, S. D.
中科院分区：
文献类型：
--
作者：
Harvey, B. S.;Nicotra, L. L.;Smid, S. D.
大麻素受体激活在动物结肠炎模型中具有保护作用。我们试图研究大麻类物质是否可以减轻人类结肠标本中的结肠炎样组织损伤，假设大麻类物质在细胞因子驱动的人类结肠粘膜损伤模型中具有保护作用。健康人结肠粘膜与促炎细胞因子肿瘤坏死因子-α和白介素1-β共同孵育，诱导结肠炎样组织损伤。同时给予氢化可的松预处理后，细胞因子引起的移行细胞和粘膜损伤的增加以及淋巴细胞密度的增加被减弱。大麻素受体2(CB2)受体选择性激动剂JWH-015显著降低细胞因子孵育后的结肠炎评分，其证据是粘膜隐窝和腔上皮损伤减少，固有层淋巴细胞密度减少。在CB2受体反向激动剂JTE-907存在下，JWH-015的作用被逆转。在细胞因子孵育的外植体结肠炎模型中，阿南达胺也有保护作用，这种保护作用与JTE-907可逆，而CB1受体激动剂ACEA则没有作用。肿瘤坏死因子-α和白介素1-β共同诱导Caco-2细胞单层细胞旁上皮通透性增加，作用超过48h。然而，CB2和CB1受体的激活都不能改变细胞因子引起的通透性增加。这些发现支持CB2受体在减轻有害的促炎细胞因子介导的人结肠粘膜损伤中的离散作用，而不直接影响粘膜上皮屏障功能。皇冠版权所有(C)2013由爱思唯尔有限公司出版。保留所有权利。
Cannabinoid receptor activation is protective in animal colitis models. We sought to investigate if cannabinoids attenuated colitis-like tissue damage in human colonic specimens, with the hypothesis that cannabinoids would be protective in a cytokine-driven model of human colonic mucosal damage. Healthy human colonic mucosa was incubated with pro-inflammatory cytokines TNF-alpha and IL-1 beta is to elicit colitis-like tissue damage. The cytokine-driven increase in scored crypt and mucosal damage and lymphocyte density was attenuated with concomitant hydrocortisone pretreatment. The cannabinoid receptor 2 (CB2) receptor-selective agonist JWH-015 significantly reduced colitis scores following cytokine incubation, as evidenced by a reduction in mucosal crypt and luminal epithelial damage and lymphocyte density in the lamina propria. The effect of JWH-015 was reversed in the presence of the CB2 receptor inverse agonist JTE-907. Anandamide was also protective in the cytokine-incubated explant colitis model in a manner reversible with JTE-907, while CB1 receptor agonism with ACEA was without effect. TNF-alpha and IL-1 beta together evoked an increase in paracellular epithelial permeability in Caco-2 cell monolayers over 48 h of incubation. However, neither CB2 nor CB1 receptor activation altered the cytokine-evoked increase in permeability. These findings support a discrete role for CB2 receptors in the attenuation of detrimental pro-inflammatory cytokine-mediated mucosal damage in the human colon without directly affecting mucosal epithelial barrier function. Crown Copyright (c) 2013 Published by Elsevier Ltd. All rights reserved.