Carnosol alleviates sepsis-induced pulmonary endothelial barrier dysfunction by targeting nuclear factor erythroid2-related factor 2/sirtuin-3 signaling pathway to attenuate oxidative damage.

Abstract

Excessive reactive oxygen species production during acute lung injury (ALI) will aggravate the inflammatory process and endothelial barrier dysfunction. Carnosol is a natural phenolic diterpene with antioxidant and anti-inflammatory properties, but its role in treating sepsis-induced ALI remains unclear. This study aims to explore the protective effects and underlying mechanisms of carnosol in sepsis-induced ALI. C57BL/6 mouse were preconditioned with carnosol for 1 h, then the model of lipopolysaccharide (LPS)-induced sepsis was established. The degree of pulmonary edema, oxidative stress, and inflammation were detected. Endothelial barrier function was evaluated by apoptosis and cell junctions. In vitro, Mito Tracker Green probe, JC-1 staining, and MitoSOX staining were conducted to investigate the effect of carnosol on mitochondria. Finally, we investigated the role of nuclear factor-erythroid 2-related factor (Nrf2)/sirtuin-3 (SIRT3) in carnosol against ALI. Carnosol alleviated LPS-induced pulmonary oxidative stress and inflammation by inhibiting excess mitochondrial reactive oxygen species production and maintaining mitochondrial homeostasis. Furthermore, carnosol also attenuated LPS-induced endothelial cell barrier damage by reducing vascular endothelial cell apoptosis and restoring occludin, ZO-1, and vascular endothelial-Cadherin expression in vitro and in vivo. In addition, carnosol increased Nrf2 nuclear translocation to promote SIRT3 expression. The protective effects of carnosol on ALI were largely abolished by inhibition of Nrf2/SIRT3. Our study has provided the first evidence that the Nrf2/SIRT3 pathway is a protective target of the endothelial barrier in ALI, and carnosol can serve as a potential therapeutic candidate for ALI by utilizing its ability to target this pathway.

• Authors: Xingbing Li, Shuo Wang, Minghao Luo, Ming Wang, Shaoping Wu, Chang Liu, Fengxian Wang, Yong Li
• Journal: Phytotherapy research : PTR (Phytother Res) Vol. 38 Issue 5 Pg. 2182-2197 (May 2024) ISSN: 1099-1573 [Electronic] England
• PMID: 38414287 (Publication Type: Journal Article)
• Copyright: © 2024 John Wiley & Sons, Ltd.

Chemical References

• NF-E2-Related Factor 2
• carnosol
• Abietanes
• Nfe2l2 protein, mouse
• Lipopolysaccharides
• Reactive Oxygen Species
• Sirtuin 3
• Sirt3 protein, mouse
• Antioxidants
• Cadherins
• cadherin 5
• Antigens, CD

Topics

• Animals
• NF-E2-Related Factor 2 (metabolism)
• Mice
• Oxidative Stress (drug effects)
• Sepsis (complications, drug therapy)
• Abietanes (pharmacology)
• Mice, Inbred C57BL
• Acute Lung Injury (drug therapy, metabolism)
• Signal Transduction (drug effects)
• Male
• Lipopolysaccharides (adverse effects)
• Reactive Oxygen Species (metabolism)
• Sirtuin 3 (metabolism)
• Apoptosis (drug effects)
• Endothelial Cells (drug effects, metabolism)
• Lung (drug effects)
• Antioxidants (pharmacology)
• Mitochondria (drug effects, metabolism)
• Cadherins (metabolism)
• Inflammation (drug therapy)
• Antigens, CD