Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis.,Mucosal Immunology

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Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2019-01-15 , DOI: 10.1038/s41385-019-0132-x
Keon-Il Im _{1,

2} , Young-Sun Nam _{1,

2} , Nayoun Kim _{1,

2} , Yunejin Song _{1,

2} , Eun-Sol Lee _{1,

2} , Jung-Yeon Lim _{1,

2} , Young-Woo Jeon _{1,

2,

3} , Seok-Goo Cho _{1,

2,

3}

Affiliation

Oral mucositis (OM) is a common complication in cancer patients undergoing anticancer treatment. Despite the clinical and economic consequences of OM, there are no drugs available for its fundamental control. Here we show that high-mobility group box 1 (HMGB1), a "danger signal" that acts as a potent innate immune mediator, plays a critical role in the pathogenesis of OM. In addition, we investigated treatment of OM through HMGB1 blockade using NecroX-7 (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1Hindole-7-yl]amine). NecroX-7 ameliorated basal layer epithelial cell death and ulcer size in OM induced by chemotherapy or radiotherapy. This protective effect of NecroX-7 was mediated by inhibition of HMGB1 release and downregulation of mitochondrial oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and macrophage inflammatory protein (MIP)-1β, as well as the expression of p53-upregulated modulator of apoptosis (PUMA) and the excessive inflammatory microenvironment, including nuclear factor-kB (NF-kB) pathways. In conclusion, our findings suggest that HMGB1 plays a key role in the pathogenesis of OM; therefore, blockade of HMGB1 by NecroX-7 may be a novel therapeutic strategy for OM.

中文翻译：

调节 HMGB1 释放可保护放化疗相关的粘膜炎。

口腔粘膜炎 (OM) 是接受抗癌治疗的癌症患者的常见并发症。尽管 OM 具有临床和经济后果，但没有可用于其基本控制的药物。在这里，我们展示了高迁移率族框 1 (HMGB1)，一种作为有效先天免疫介质的“危险信号”，在 OM 的发病机制中起着关键作用。此外，我们使用 NecroX-7 (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1Hindole-7-yl 研究了通过 HMGB1 阻断 OM 的治疗]胺）。NecroX-7 改善了化疗或放疗诱导的 OM 基底层上皮细胞死亡和溃疡大小。NecroX-7 的这种保护作用是通过抑制 HMGB1 释放和下调线粒体氧化应激来介导的。此外，NecroX-7 抑制 HMGB1 诱导的肿瘤坏死因子-α (TNF-α)、白细胞介素 (IL)-1β 和巨噬细胞炎症蛋白 (MIP)-1β 的释放，以及 p53 上调的细胞凋亡调节剂的表达(PUMA) 和过度炎症微环境，包括核因子-kB (NF-kB) 通路。总之，我们的研究结果表明 HMGB1 在 OM 的发病机制中起着关键作用；因此，NecroX-7 对 HMGB1 的阻断可能是 OM 的一种新的治疗策略。我们的研究结果表明 HMGB1 在 OM 的发病机制中起着关键作用；因此，NecroX-7 对 HMGB1 的阻断可能是 OM 的一种新的治疗策略。我们的研究结果表明 HMGB1 在 OM 的发病机制中起着关键作用；因此，NecroX-7 对 HMGB1 的阻断可能是 OM 的一种新的治疗策略。

更新日期：2019-05-16

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