Resveratrol alleviates lipopolysaccharide-induced acute lung injury through blocking the excessive autophagy/mitophagy via SIRT1/PGC-1α and TNF/NF-κB/JNK pathways.

Acute lung injury (ALI) is a hypoxic respiratory insufficiency disease characterized by oxidative damage, inflammatory response, and autophagic cell death. Resveratrol (Res) modulates the autophagy activation and excessive autophagy inhibition to counteract oxidative stress, yet the latter mechanism has been vague. Herein, effects and regulatory mechanisms of Res on lung injury, inflammation, and autophagy/mitophagy were explored in lipopolysaccharide (LPS)-stimulated rats and RAW264.7 cells. Transcriptome data exhibited that, Res influenced oxidative stress, inflammation, apoptosis, necroptosis, proliferation, and migration probably through TNF/NF-kB-mediated phagosome and lysosome formations in ALI rats. In subsequent assays, Res significantly reversed the LPS-induced lung injury and mitochondrial dysfunction via activating the SIRT1/PGC-1α pathway. Also, Res reduced LPS-triggered inflammatory cytokines through restraining the TNF/NF-κB/JNK pathway. Importantly, Res attenuated excessive LC3/ATG5/p62-mediated autophagy and PINK1/Parkin-adjusted mitophagy, decreasing the autophagic flux by inactivating the NF-κB pathway. Thus, Res augmented anti-oxidative and anti-inflammatory effects most likely through ameliorating the excessive autophagy/mitophagy via two converging pathways (SIRT1/PGC-1α and TNF/NF-κB/JNK). Notably, Res down-regulated the DNMT2/TRDMT1 expression and probably adopted a similar binding pattern with plant flavonoids to block this enzyme. Altogether, these findings will provide a novel mechanism and therapeutic strategy for ALI or related lung diseases by Res-modulated autophagy/mitophagy inactivation and DNMT2/TRDMT1 inhibition.