丹参酮IIA + 蛇床子素通过Keap1-Nrf2/HO-1途径减轻脂多糖诱导的急性肺损伤中的铁死亡。

Tanshinone IIA + Osthole alleviates ferroptosis in LPS-induced acute lung injury by Keap1-Nrf2/HO-1 pathway.

作者信息

Li Yujuan, Pan Lei, Zhao Qi, Xiong Huanqing, Fang Xiaoan, Guo Xian, Wang Ying, Su Xiaorong, Liu Pan, Hao Jing, Wang Lei, Wang Xinqun, Dong Quandi, Li Zhichao, Jin Faguang

机构信息

Department of Pulmonary and Critical Care Medicine, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China.

Department of Endocrinology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China.

出版信息

Microb Pathog. 2025 Jun;203:107347. doi: 10.1016/j.micpath.2025.107347. Epub 2025 Mar 25.

DOI:10.1016/j.micpath.2025.107347

PMID:40147558

Abstract

BACKGROUND

Acute lung injury (ALI) is associated with a high mortality rate and requires effective treatment. Tanshinone IIA (T) and Osthole (O) exhibit anti-inflammatory effects and have been used to protect against lipopolysaccharide (LPS)-induced lung injury in mice. However, the combined effects of T and O on lung injury protection and their potential protective mechanisms have not been studied.

OBJECTIVE

To assess the protective effects of TO on LPS-induced ALI in mice and BEAS-2B cell injury and to investigate the potential mechanisms underlying these protective effects.

METHODS

Models of ALI induced by LPS were established. The assessment encompassed the viability of BEAS-2B cells, cell count, myeloperoxidase (MPO) activity, protein content, as well as IL-6 and TNF-a levels in bronchoalveolar lavage fluid (BALF). Additionally, malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) levels in mouse lung tissue were measured. The effects of TO were assessed using immunofluorescence (IF), immunohistochemistry (IHC), Western Blot (WB), RT-PCR, and ELISA. Statistical analysis involved one-way ANOVA and t-test.

RESULTS

TO administration led to a significant reduction in lung edema (W/D), MDA, ROS, GSH, and superoxide dismutase (SOD) levels compared to the individual T or O groups, alleviating LPS-induced ALI. TO also significantly attenuated lung tissue damage, reduced inflammatory response, decreased Fe and 4-HNE levels, and increased GPX4, SLC7A11, and Nrf2 gene expression in mice. Ultimately, TO alleviated ferroptosis in LPS-induced ALI by activating Nrf2 expression, and no markedly adverse reactions were observed.

CONCLUSION

TO alleviates LPS-induced ALI and effectively treats against LPS-induced ALI.

摘要

背景

急性肺损伤（ALI）死亡率高，需要有效治疗。丹参酮IIA（T）和蛇床子素（O）具有抗炎作用，已被用于保护小鼠免受脂多糖（LPS）诱导的肺损伤。然而，T和O对肺损伤保护的联合作用及其潜在保护机制尚未得到研究。

目的

评估TO对LPS诱导的小鼠ALI及BEAS-2B细胞损伤的保护作用，并探讨这些保护作用的潜在机制。

方法

建立LPS诱导的ALI模型。评估包括BEAS-2B细胞活力、细胞计数、髓过氧化物酶（MPO）活性、蛋白质含量以及支气管肺泡灌洗液（BALF）中IL-6和TNF-α水平。此外，还测量了小鼠肺组织中丙二醛（MDA）、活性氧（ROS）和谷胱甘肽（GSH）水平。使用免疫荧光（IF）、免疫组织化学（IHC）、蛋白质印迹法（WB）、逆转录-聚合酶链反应（RT-PCR）和酶联免疫吸附测定（ELISA）评估TO的作用。统计分析采用单因素方差分析和t检验。

结果

与单独的T或O组相比，给予TO可显著降低肺水肿（W/D）、MDA、ROS、GSH和超氧化物歧化酶（SOD）水平，减轻LPS诱导的ALI。TO还显著减轻肺组织损伤，减少炎症反应，降低铁和4-羟基壬烯醛（4-HNE）水平，并增加小鼠体内谷胱甘肽过氧化物酶4（GPX4）、溶质载体家族7成员11（SLC7A11）和核因子E2相关因子2（Nrf2）基因表达。最终，TO通过激活Nrf2表达减轻LPS诱导的ALI中的铁死亡，且未观察到明显不良反应。