10-Hydroxy-2-decenoic acid ameliorates LPS-induced acute lung injury through targeting MD2-mediated inflammatory signaling pathways.

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-10-04 DOI:10.1016/j.taap.2025.117589

Cong Shu, Chen Li, Huamin Liu, Zengxian Zhou, Chenghao Qian, Zhuohui Xie, Fenfen Lin, Yuxiao Jiang, Ruping Chen, Yue Liu, Xin Liu, Gaozhi Chen, Lili Fu

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引用次数: 0

Abstract

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are life-threatening conditions with high mortality, characterized by excessive inflammatory responses. Lipopolysaccharide (LPS) is widely used to mimic ALI by activating myeloid differentiation factor 2 (MD2)/Toll-like receptor 4 (TLR4)-mediated inflammatory pathways. Royal jelly-derived 10-hydroxy-2-decenoic acid (10-HDA) exhibits anti-inflammatory properties, but its role in ALI remains unexplored.

Objective: This study aimed to investigate the therapeutic potential of 10-HDA against LPS-induced ALI and elucidate its underlying mechanism.

Methods: In vitro, mouse peritoneal macrophages (MPMs) were pretreated with 10-HDA before LPS stimulation. In vivo, ALI was induced in mice via intratracheal LPS, with 10-HDA administered intraperitoneally. Cytokine levels were measured via ELISA and qPCR. Signaling pathways were analyzed by Western blot and immunofluorescence. Lung injury, inflammatory cell infiltration, and edema were assessed via histopathology, BALF analysis, and wet/dry ratio. Immunoprecipitation, molecular docking, and drug affinity-responsive target stability (DARTS) assays were used to identify the interaction between 10-HDA and MD2.

Results: 10-HDA significantly suppressed LPS-induced proinflammatory cytokine secretion in MPMs and ALI mice, and inhibited phosphorylation of TAK1, MAPKs, TBK1 and NF-κB nuclear translocation. It attenuated lung histopathological damage, neutrophil infiltration, and edema. Mechanistically, 10-HDA disrupted MD2/TLR4-mediated inflammatory pathways by directly binding MD2, as confirmed by immunoprecipitation, DARTS, and molecular docking.

Conclusion: 10-HDA alleviates LPS-induced ALI by targeting MD2 to block TLR4 signaling, thereby suppressing both MyD88-dependent (MAPKs/NF-κB) and TRIF-dependent (TBK1/IRF3) pathways. These findings highlight 10-HDA as a promising therapeutic candidate for ALI/ARDS.

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10-羟基-2-十烯酸通过靶向md2介导的炎症信号通路改善lps诱导的急性肺损伤。

背景：急性肺损伤（ALI）及其严重形式急性呼吸窘迫综合征（ARDS）是危及生命的高死亡率疾病，其特征是过度的炎症反应。脂多糖（LPS）被广泛用于通过激活髓样分化因子2 (MD2)/ toll样受体4 （TLR4）介导的炎症途径来模拟ALI。蜂王浆衍生的10-羟基-2-十烯酸（10-HDA）具有抗炎特性，但其在ALI中的作用尚不清楚。目的：探讨10-HDA对脂多糖诱导的ALI的治疗潜力，并阐明其作用机制。方法：在LPS刺激前用10-HDA预处理小鼠腹腔巨噬细胞（MPMs）。在体内，通过气管内LPS诱导小鼠ALI，腹腔内给予10-HDA。采用ELISA和qPCR检测细胞因子水平。Western blot和免疫荧光分析信号通路。通过组织病理学、BALF分析和湿/干比评估肺损伤、炎症细胞浸润和水肿。利用免疫沉淀、分子对接和药物亲和反应靶稳定性（dart）检测确定10-HDA与MD2之间的相互作用。结果：10-HDA显著抑制lps诱导的MPMs和ALI小鼠促炎细胞因子分泌，抑制TAK1、MAPKs、TBK1磷酸化和NF-κB核易位。它减轻了肺组织病理损伤、中性粒细胞浸润和水肿。在机制上，10-HDA通过直接结合MD2破坏MD2/ tlr4介导的炎症通路，免疫沉淀、dart和分子对接证实了这一点。结论：10-HDA通过靶向MD2阻断TLR4信号通路，从而抑制myd88依赖性（MAPKs/NF-κB）和trif依赖性（TBK1/IRF3）通路，减轻lps诱导的ALI。这些发现强调了10-HDA作为ALI/ARDS的有希望的治疗候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.