激活血管紧张素转换酶 2 (ACE2) 在脓毒症相关急性呼吸窘迫综合征 (ARDS) 的发病机制中发挥着重要作用。迷迭香酸 (RA) 作为源自迷迭香的一种重要的多酚次级代谢产物，在脓毒症中调节 ACE2 的作用尚不清楚，尽管其对 ACE 抑制和脓毒症相关肺损伤的影响已被探索。该研究调查了脂多糖 (LPS) 诱导的小鼠肺和 BEAS2B 细胞中 ACE2 的表达。此外，还采用分子对接、蛋白质-蛋白质相互作用（PPI）网络分析和蛋白质印迹来预测和评估RA在体内和体外对LPS诱导的铁死亡的分子机制。卡托普利预处理可逆转 LPS 诱导的谷胱甘肽过氧化物酶 4 (GPX4) 下调、ACE/ACE2 失衡以及呼吸频率 (BPM)、每分钟通气量 (MV) 和 50% 呼气量 (EF50) 时的呼气流量 (EF50) 的改变体外和体内。在 LPS 诱导的小鼠 ARDS 中，RA 显着抑制中性粒细胞和单核细胞向肺部的浸润，增加 GPX4 和 ACE2 蛋白的数量，改善肺功能，并降低炎症细胞因子水平和 ER 应激。分子对接显示 RA 能够与 ACE 和 ACE2 相互作用。此外，与不同的药物抑制剂联合阻断ACE和铁死亡，RA仍显着抑制炎症细胞因子白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和C-X-C基序趋化因子2（CXCL2）水平，以及改善肺功能和增强 GPX4 表达。特别是，RA 在 LPS 诱导的脓毒症 ARDS 中的抗铁死亡作用是 RAS 依赖性的。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Activating angiotensin-converting enzyme 2 (ACE2) is an important player in the pathogenesis of septic-related acute respiratory distress syndrome (ARDS). Rosmarinic acid (RA) as a prominent polyphenolic secondary metabolite derived from Rosmarinus officinalis modulates ACE2 in sepsis remains unclear, although its impact on ACE inhibition and septic-associated lung injury has been explored. The study investigated the ACE2 expression in lipopolysaccharide (LPS)-induced lungs in mice and BEAS2B cells. Additionally, molecular docking, protein-protein interaction (PPI) network analysis, and western blotting were employed to predict and evaluate the molecular mechanism of RA on LPS-induced ferroptosis in vivo and in vitro. LPS-induced glutathione peroxidase 4 (GPX4) downregulation, ACE/ACE2 imbalance, and alteration of frequency of breathing (BPM), minute volume (MV), and the expiratory flow at 50% expired volume (EF50) were reversed by captopril pretreatment in vitro and in vivo. RA notably inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of GPX4 and ACE2 proteins, lung function improvement, and decreased inflammatory cytokines levels and ER stress in LPS-induced ARDS in mice. Molecular docking showed RA was able to interact with ACE and ACE2. Moreover, combined with different pharmacological inhibitors to block ACE and ferroptosis, RA still significantly inhibited inflammatory cytokines Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and C-X-C motif chemokine 2 (CXCL2) levels, as well as improved lung function, and enhanced GPX4 expression. Particularly, the anti-ferroptosis effect of RA in LPS-induced septic ARDS is RAS-dependent.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.