Celastrol ameliorates lipopolysaccharide (LPS)-induced acute lung injury by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism.

Acute lung injury (ALI) is a devastating clinical syndrome without effective therapy. Celastrol, as a natural anti-inflammatory compound, has showed therapeutic potential against inflammatory diseases. In this study, we have investigated the potential effect of Celastrol on lipopolysaccharide (LPS)-induced ALI. C57BL/6J mice, Nrf1-knockout mice and A549 (human alveolar epithelial cell line) cells were used to investigate the protective role of Celastrol in LPS-induced ALI. Our data showed that administration of Celastrol significantly alleviated lung pathologic injury and increased the survival rate, which was associated with the improvement of mitochondrial function in the injured lung. Moreover, Celastrol enhanced phosphorylation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear translocation of nuclear respiratory factor 1 (Nrf1) and subsequent up-regulation of its downstream mitochondria electron transport chain complex I (NDUF) gene expression, which induced an increase in mitochondrial complex Ⅰ activity. The beneficial effects of Celastrol on regulation of Nrf1 were abolished by inhibition of AMPK and PGC-1α. Finally, in Nrf1 deficient mice, the protective effects of Celastrol on LPS-induced ALI were largely vanished. Our data indicated that Celastrol can prevent LPS-induced ALI by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism, suggesting that Celastrol may represent a novel therapeutic potential for LPS-induced ALI. [Display omitted] • Celastrol ameliorates LPS-induced acute lung injury in mouse model. • Celastrol improves mitochondrial function in mouse model with LPS-induced acute lung injury. • Celastrol activates AMPK/PGC-1α/Nrf1 signal pathway in LPS-induced acute lung injury. • The protective effects of Celastrol on LPS-induced acute lung injury are largely vanished in Nrf1 deficient mice. [ABSTRACT FROM AUTHOR]