Shandong University of Traditional Chinese Medicine, Shandong, 250002, People's Republic of China.
Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine Shandong University, Shandong, 250033, People's Republic of China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Jan;397(1):99-108. doi: 10.1007/s00210-023-02589-0. Epub 2023 Jun 27.
Acute respiratory distress syndrome (ARDS) is a devastating respiratory disorder, characterized by overwhelming inflammation in the alveoli without effective pharmacological treatment. We aimed to investigate the effect and mechanism of angiotensin II type 2 receptor (AT2R) agonist, Compound 21 (C21), on the lipopolysaccharide (LPS)-induced acute lung injury (ALI) model. The protective effect of C21 was evaluated via enzyme-linked immunosorbent assay (ELISA), Western blot (WB), real-time PCR, and fluorescence microscopy in LPS-challenged THP1-derived macrophages. Besides, the in vivo efficacy of C21 was assessed using cell counting, ELISA, protein quantification, hematoxylin-eosin (H&E) staining, and WB in an LPS-induced ALI mouse model. The results showed that C21 significantly inhibited the secretion of pro-inflammatory cytokines (CCL-2, IL-6), overproduction of intracellular ROS, and activation of inflammatory pathways (NF-κB/NLRP3, p38/MAPK) in THP-1 cell-derived macrophages stimulated by LPS. In in vivo study, intraperitoneal injection of C21 could reduce airway leukocytes accumulation and chemokine/cytokine (keratinocyte chemoattractant (KC), IL-6) generation, as well as alleviate diffuse alveolar damage induced by LPS. Conclusively, the AT2R agonist C21 significantly inhibited LPS-stimulated excess inflammatory responses and oxidative stress in macrophages. Meanwhile, C21 could effectively alleviate acute inflammation and tissue damage in the lungs of ALI mice challenged by LPS. The results of this study bring new hope for the early treatment of ALI/ARDS.
急性呼吸窘迫综合征（ARDS）是一种破坏性的呼吸系统疾病，其特征是肺泡内弥漫性炎症，但目前尚无有效的药物治疗方法。本研究旨在探讨血管紧张素 II 型受体（AT2R）激动剂化合物 21（C21）对脂多糖（LPS）诱导的急性肺损伤（ALI）模型的作用及机制。通过酶联免疫吸附试验（ELISA）、Western blot（WB）、实时 PCR 和荧光显微镜检测 LPS 刺激的 THP1 衍生巨噬细胞中 C21 的保护作用。此外，还通过细胞计数、ELISA、蛋白定量、苏木精-伊红（H&E）染色和 WB 评估 LPS 诱导的 ALI 小鼠模型中 C21 的体内疗效。结果表明，C21 可显著抑制 LPS 刺激的 THP-1 细胞衍生巨噬细胞中促炎细胞因子（CCL-2、IL-6）的分泌、细胞内 ROS 的过度产生以及炎症途径（NF-κB/NLRP3、p38/MAPK）的激活。在体内研究中，腹腔注射 C21 可减少气道白细胞聚集和趋化因子/细胞因子（角质细胞趋化因子（KC）、IL-6）的产生，并减轻 LPS 引起的弥漫性肺泡损伤。综上所述，AT2R 激动剂 C21 可显著抑制 LPS 刺激的巨噬细胞过度炎症反应和氧化应激。同时，C21 可有效减轻 LPS 诱导的 ALI 小鼠肺部的急性炎症和组织损伤。本研究结果为 ALI/ARDS 的早期治疗带来了新的希望。
