Synergistic Action of Diclofenac with Endotoxin-Mediated Inflammation Exacerbates Intestinal Injury in Vitro.
Synergistic Action of Diclofenac with Endotoxin-Mediated Inflammation Exacerbates Intestinal Injury in Vitro.
复制标题
双氯芬酸与内毒素介导炎症的协同作用加重体外肠道损伤。
DOI：
10.1021/acsinfecdis.0c00762
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发表时间：
2021-04-09
影响因子：
5.3
通讯作者：
Carrier, Rebecca L.
中科院分区：
文献类型：
--
作者：
Chen, Wen Li Kelly;Suter, Emily;Miyazaki, Hikaru;Velazquez, Jason;Lauffenburger, Douglas A.;Griffith, Linda G.;Carrier, Rebecca L.
关键词：
肠道内环境的稳定受到多种细胞类型的协调作用的严格调控，包括肠细胞、杯状细胞和免疫细胞。肠道屏障功能的破坏可以增加对病原体入侵的易感性，破坏微生物-上皮-免疫系统的共生相互作用，表现在各种肠道和全身病理中。然而，对这些类型的细胞如何沟通并共同促进健康和疾病中的组织功能缺乏定量的了解。在这里，我们利用人类肠上皮-树突状细胞模型和分泌因子的多变量分析来研究细胞对生理和/或病理信号(如内毒素、非类固醇抗炎药物(NSAID))的反应。具体地说，我们证明了双氯芬酸(DCF)的治疗，一种通常用于治疗与急性感染和其他情况相关的炎症的非甾体抗炎药，当单独服用时，全局抑制细胞因子的分泌。然而，DCF诱导的屏障功能的破坏允许腔内脂多糖(LPS)的移位和常驻免疫细胞的激活，从而压倒了DCF的抗炎作用。DCF促进的炎症在一定程度上是通过上调巨噬细胞移动抑制因子(MIF)介导的，巨噬细胞移动抑制因子是天然免疫的重要调节因子。然而，虽然MIF活性的中和可以使炎症恢复正常，但它并没有导致肠道愈合。我们的数据表明，仅有系统范围的炎症抑制不足以实现粘膜愈合，特别是在存在DCF的情况下，DCF的靶点COX-前列腺素途径是粘膜动态平衡的核心。事实上，损伤后去除DCF可以使肠上皮功能部分恢复，这一恢复阶段与细胞因子和趋化因子亚群的上调有关，暗示它们对肠道愈合有潜在贡献。这些结果突出了捕获免疫功能的肠道模型的实用性，结合多变量分析，在了解控制对微生物因素的反应的分子机制方面，支持在研究宿主-病原体相互作用方面的应用。利用人肠上皮-树突状细胞模型研究了生理和/或病理信号(如脂多糖(LPS)和非类固醇抗炎药(NSAID)双氯芬酸(DCF))对细胞串扰的影响。DCF诱导的屏障功能破坏允许内毒素移位和激活常驻免疫细胞，从而凌驾于DCF的抗炎影响之上。
Intestinal homeostasis is tightly regulated by the orchestrated actions of a multitude of cell types, including enterocytes, goblet cells and immune cells. Disruption of intestinal barrier function can increase susceptibility to pathogen invasion and destabilize commensal microbial-epithelial-immune interaction, manifesting in various intestinal and systemic pathologies. However, a quantitative understanding of how these cell types communicate and collectively contribute to tissue function in health and disease is lacking. Here, we utilized a human intestinal epithelial-dendritic cell model and multivariate analysis of secreted factors to investigate the cellular crosstalk in response to physiological and/or pathological cues (e.g., endotoxin, non-steroidal anti-inflammation drug (NSAID)). Specifically, we demonstrated that treatment with diclofenac (DCF), an NSAID commonly used to treat inflammation associated with acute infection and other conditions, globally suppressed cytokine secretion when dosed in isolation. However, the disruption of barrier function induced by DCF allowed for luminal lipopolysaccharide (LPS) translocation and activation of resident immune cells that overrode the anti-inflammatory influence of DCF. DCF-facilitated inflammation in the presence of LPS was in part mediated by upregulation of macrophage migration inhibitory factor (MIF), an important regulator of innate immunity. However, while neutralization of MIF activity normalized inflammation, it did not lead to intestinal healing. Our data suggest that systems-wide suppression of inflammation alone is insufficient to achieve mucosal healing, especially in the presence of DCF, the target of which, the COX-prostaglandin pathway, is central to mucosal homeostasis. Indeed, DCF removal post-injury enabled partial recovery of intestinal epithelium functions, and this recovery phase was associated with upregulation of a subset of cytokines and chemokines, implicating their potential contribution to intestinal healing. The results highlight the utility of an intestinal model capturing immune function, coupled with multivariate analysis, in understanding molecular mechanisms governing response to microbial factors, supporting application in studying host-pathogen interactions. A human intestinal epithelial-dendritic cell model was utilized to investigate cellular crosstalk in response to physiological and/or pathological cues (e.g., lipopolysaccharide (LPS) and the non-steroidal anti-inflammation drug (NSAID) diclofenac (DCF). Disruption of barrier function induced by DCF allowed for LPS translocation and activation of resident immune cells that overrode the anti-inflammatory influence of DCF.
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影响因子：
2.4
作者：
Bischoff SC;Barbara G;Buurman W;Ockhuizen T;Schulzke JD;Serino M;Tilg H;Watson A;Wells JM
通讯作者：
Wells JM
影响因子：
29.4
作者：
Brand, S;Sakaguchi, T;Reinecker, HC
通讯作者：
Reinecker, HC
影响因子：
38.3
作者：
Mahler, Gretchen J.;Esch, Mandy B.;Shuler, Michael L.
通讯作者：
Shuler, Michael L.
DOI：
10.1124/jpet.106.103994
发表时间：
2006-08-01
影响因子：
3.5
作者：
Hatazawa, Ryo;Ohno, Ryoko;Takeuchi, Koji
通讯作者：
Takeuchi, Koji
影响因子：
--
作者：
Fukui, Hiroshi
通讯作者：
Fukui, Hiroshi