Abstract
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.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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This work was supported by the National Natural Science Foundation of China (grant number: 82000086), Shanghai Sailing Program (grant number: 20YF1440300) for Wei Gao.
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QL is responsible for the study. LC, PG, YS, LM, and MW coordinated to conduct experiments with the guidance from WG and QL. LC, PG, and YS wrote and revised the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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All animal procedures were approved by the Management and Ethics Committee of the Laboratory Animal Research Center of Tongji University (Permit Number: TJBB03721106). All procedures on mice were performed under anesthesia, and all efforts were made to minimize the animal suffering.
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Chen, L., Gong, P., Su, Y. et al. Angiotensin II type 2 receptor agonist attenuates LPS-induced acute lung injury through modulating THP-1-derived macrophage reprogramming. Naunyn-Schmiedeberg's Arch Pharmacol 397, 99–108 (2024). https://doi.org/10.1007/s00210-023-02589-0
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DOI: https://doi.org/10.1007/s00210-023-02589-0