Perillaldehyde ameliorates lipopolysaccharide-induced acute lung injury via suppressing the cGAS/STING signaling pathway.

ABSTRACT

Acute lung injury (ALI) is a common life-threatening illness characterized by a lung inflammatory response and oxidative stress, and effective agent therapies are currently lacking. mtDNA can be recognized by cGAS/STING, the dysregulation of which leads to inflammatory diseases, such as ALI. Perillaldehyde(PAH), one of the major active components of traditional Chinese medicine made from Perilla frutescens, has antioxidant and antiinflammatory effects. The aim of this study was to explore whether PAH can protect against lipopolysaccharide (LPS)-induced ALI and whether its protective effect is exerted through the regulation of cGAS/STING signaling. We found that PAH significantly inhibited lung histological changes, inflammatory cell infiltration, and the overproduction of inflammatory cytokines induced by LPS. Moreover, PAH inhibited LPS-induced oxidative stress, as shown by the deceases in superoxide dismutase (SOD) and glutathione(GSH) levels and increased in malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels. In addition, PAH markedly downregulated the expression of cGAS, STING, p-TBK, p-IRF3, p-P65, and p-IκB, and pharmacological inhibition of cGAS/STING inhibited ALI- induced by LPS. Furthermore, the levels of mitochondrial ROS (mROS) and mtDNA were increased, and cGAS/STING-mediated IRF3/NF-κB signaling was activated during the inflammatory response- induced by LPS in RAW264.7 cells. In addition, pretreatment with the STING activator partially abolished the inhibitory effect of PAH on the inflammation and activation of STING-mediated IRF3/NF-κB signaling induced by LPS. Overall, the results revealed that PAH can effectively alleviate ALI by inhibiting cGAS/STING-mediated IRF3/NF-κB signaling, and that PAH may be a potential candidate agent for the treatment of ALI.