Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China.
Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China; Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan and Education Ministry of P.R., Henan University of Chinese Medicine, Zhengzhou 450046, China.
Phytomedicine. 2022 Oct;105:154386. doi: 10.1016/j.phymed.2022.154386. Epub 2022 Aug 10.
Severe inflammation of the lungs results from acute lung injury (ALI), a common life-threatening lung disease with a high mortality rate. The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays essential roles in diverse biological processes including inflammation, metabolism, development, and immune response. Salvianolactone acid A (SA) is a terpenoid derived from the herb Salvia miltiorrhiza. However, there is a scarcity of experimental evidence indicating whether the effect of SA on ALI occurs via PPAR-γ.
SA (20 or 40 mg/kg, i.g., 1 time/day) was administered to mice for 3 d, followed by the induction of ALI by intranasal lipopolysaccharide (LPS, 10 mg/kg). The lung function and levels of inflammation, reactive oxygen species (ROS), immune cells, apoptosis, and PPAR-γ were examined. The antagonistic activity of GW9662 (GW, 1 µM, specific PPAR-γ blocker) and PPAR-γ transfection silencing against SA (10 μM) in BEAS-2B cells induced by LPS (10 μg/ml, 24 h) was also investigated to assess whether the observed effects caused by SA were mediated by PPAR-γ.
The results showed that lung histopathological injury, the B-line, the fluorescence intensity of live small animal, and the biomarkers in BALF or lung in the treatment of SA could regulate significantly. In addition, SA obviously decreased the levels of ROS and apoptosis in the primary lung cells, and MDA, increased the levels of GSH-Px and SOD. SA reduced levels of macrophages and neutrophils. Furthermore, SA reduced the protein levels of Keap-1, Cleaved-caspase-3, Cleaved-caspase-9, p-p65/p65, NLRP3, IL-1β, and upregulated the levels of p-Nrf2/Nrf2, HO-1, Bcl-2/Bax, PPAR-γ, p-AMPK/AMPK in lung tissue. In addition, silencing and inhibition of PPAR-γ effectively decreased the protective effects of SA in BEAS-2B cells induced by LPS, which might indicate that the active molecules of SA regulate ALI via mediation by PPAR-γ, which exhibited that the effect of SA related to PPAR-γ.
The anti-ALI effects of SA were partially mediated through PPAR-γ signaling. These data provide the molecular justification for the usage of SA in treating ALI and can assist in increasing the comprehensive utilization rate of Salvia miltiorrhiza.
急性肺损伤（ALI）导致肺部严重炎症，这是一种常见的致命性肺部疾病，死亡率很高。配体激活的转录因子过氧化物酶体增殖物激活受体（PPAR）γ在多种生物过程中发挥着重要作用，包括炎症、代谢、发育和免疫反应。丹酚酸 A（SA）是一种源自丹参的萜类化合物。然而，目前还缺乏实验证据表明 SA 对 ALI 的影响是否通过 PPAR-γ 发生。
用 20 或 40 mg/kg 的 SA（ig，每天 1 次）处理小鼠 3 天，然后用鼻内脂多糖（LPS，10 mg/kg）诱导 ALI。检测肺功能、炎症水平、活性氧（ROS）、免疫细胞、细胞凋亡和 PPAR-γ。还研究了 GW9662（GW，1 μM，PPAR-γ 特异性阻滞剂）和 PPAR-γ 转染沉默对 LPS（10 μg/ml，24 h）诱导的 BEAS-2B 细胞中 SA（10 μM）的拮抗作用，以评估 SA 观察到的作用是否由 PPAR-γ 介导。
结果表明，SA 可显著调节肺组织病理损伤、B 线、小动物荧光强度和 BALF 或肺中的生物标志物。此外，SA 明显降低原代肺细胞中 ROS 和细胞凋亡的水平，降低 MDA，增加 GSH-Px 和 SOD 的水平。SA 减少巨噬细胞和中性粒细胞的水平。此外，SA 降低了 Keap-1、Cleaved-caspase-3、Cleaved-caspase-9、p-p65/p65、NLRP3、IL-1β 的蛋白水平，并上调了肺组织中 p-Nrf2/Nrf2、HO-1、Bcl-2/Bax、PPAR-γ、p-AMPK/AMPK 的水平。此外，沉默和抑制 PPAR-γ 可有效降低 LPS 诱导的 BEAS-2B 细胞中 SA 的保护作用，这可能表明 SA 的活性分子通过 PPAR-γ 调节 ALI，表明 SA 与 PPAR-γ 相关的作用。
SA 的抗 ALI 作用部分通过 PPAR-γ 信号传导介导。这些数据为 SA 治疗 ALI 的应用提供了分子依据，并有助于提高丹参的综合利用率。
