Matrine alleviates oxidative stress and ferroptosis in severe acute pancreatitis-induced acute lung injury by activating the UCP2/SIRT3/PGC1α pathway

• Published in: International immunopharmacology 2023-04, Vol.117, p.109981-109981, Article 109981
• Main Authors: Jin, Hongzhong, Zhao, Kailiang, Li, Juanjuan, Xu, Zhiliang, Liao, Shichong, Sun, Shengrong
• Format: Article
• Language: English
• Subjects: Acute Disease; Acute lung injury; Acute Lung Injury - chemically induced; Acute pancreatitis; Animals; Antioxidants - pharmacology; Ferroptosis; Inflammation - pathology; Lipopolysaccharides - pharmacology; Matrine; Matrines; Mice; Mice, Inbred C57BL; Oxidative Stress; Pancreatitis - complications; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Reactive Oxygen Species - metabolism; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; UCP2
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.109981

•SAP induces oxidative stress and ferroptosis in lung tissue.•Matrine alleviates oxidative stress and ferroptosis in SAP-ALI.•Matrine alleviates oxidative stress and ferroptosis via activates UCP2/SIRT3/PGC1α pathway. Acute lung injury (ALI) is one of the most serious complications of severe acute pancreatitis (SAP). Matrine is well known for its powerful antioxidant and antiapoptotic properties, although its specific mechanism of action in SAP-ALI is unknown. In this study, we examined the effects of matrine on SAP-associated ALIand the specific signaling pathways implicated in SAP-induced ALI, such as oxidative stress, the UCP2-SIRT3-PGC1α pathway, and ferroptosis. The administration of caerulein and lipopolysaccharide (LPS) to UCP2-knockout (UCP2−/−) and wild-type (WT) mice that were pretreated with matrine resulted in pancreatic and lung injury. Changes in reactive oxygen species (ROS) levels, inflammation, and ferroptosis in BEAS-2B and MLE-12 cells were measured following knockdown or overexpression and LPS treatment. Matrine inhibited excessive ferroptosis and ROS production by activating the UCP2/SIRT3/PGC1α pathway while reducing histological damage, edema, myeloperoxidase activity and proinflammatory cytokine expression in the lung. UCP2 knockout decreased the anti-inflammatory properties of matrine and reduced the therapeutic effects of matrine on ROS accumulation and ferroptosis hyperactivation. LPS-induced ROS production and ferroptosis activation in BEAS-2B cells and MLE-12 cells were further enhanced by knockdown of UCP2, but this effect was rescued by UCP2 overexpression. This study demonstrated that matrine reduced inflammation, oxidative stress, and excessive ferroptosis in lung tissue during SAP by activating the UCP2/SIRT3/PGC1α pathway, demonstrating its therapeutic potential in SAP-ALI.