(1600) Effect of FUNDC1 Autophagy-Mediated cGAS/STING Pathway in Oleic Acid-Induced Acute Lung Injury

Introduction: The pathogenesis of acute lung injury involves the aggregation, activation and release of a variety of inflammatory cytokines and chemokines of various key effector cells. This study will explore the mechanism of mitophagy and cGAS/STING pathway in oleic acid-induced acute lung injury.

Methods: The mice and pulmonary microvascular endothelial cells were divided into the control group, the acute lung injury group, the FUNDC1- control group and the FUNDC1- acute lung injury group. Hematoxylin eosin staining was performed on the lung tissue. The autophagosomes were observed by electron microscope and mtDNA was detected by qPCR. Western blot was used to quantitatively analyze the protein expression differences of pathways cGAS, STING, pTBK1, pIRF3 and pNF-κB. The serum IFN-β expression level was detected by ELISA. The morphological changes of cells were observed under the microscope. The LDH level and the expressions of F-actin and ZO-1 as well as cGAS and STING in endothelial cells were observed.

Results: Compared with the control group, the pathological changes of lung injury group were significantly aggravated. The expressions of cGAS, STING, pIRF3 and pNF-κB in lung tissues of mice with acute lung injury were significantly higher, serum IFN-β is also increased. The morphology of lung microvascular endothelial cells changed from polygonal to circular and the expression of LDH in cell supernatant was increased. The expressions of endothelial F-actin and ZO-1 were decreased, indicating that the endothelial permeability was worse. After the FUNDC1 gene was knocked out to inhibit mitochondrial autophagy, it could be seen that the autophagosomes were significantly reduced and the mtDNA in cell supernatant was increased. The expression levels of pathway proteins in lung tissues and cells of FUNDC1- acute lung injury group were higher than those in the wild-type acute lung injury group and the expression of serum IFN-β was also increased.

Conclusions: The silence of FUNDC1 inhibits mitophagy, subsequently the accumulated mtDNA activates cGAS/STING pathway to aggravate the pathological damage and inflammatory response in acute lung injury group, suggesting that mitophagy may have a protective effect in oleic acid-induced acute lung injury through cGAS/STING pathway.