Peroxisome proliferator-activated receptor gamma coactivator-1α/HSF1 axis effectively alleviates lipopolysaccharide-induced acute lung injury via suppressing oxidative stress and inflammatory response.

Acute lung injury (ALI) interferes with lung function by causing pulmonary inflammation and oxidative stress. Suppressing intracellular reactive oxygen species (ROS) may block intracellular inflammation. Thus, the purpose of the current study was to investigate the roles of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1 alpha)/HSF1 axis in an lipopolysaccharide (LPS)-induced ALI murine model and in RAW264.7 macrophages. In the LPS-administrated mouse model, the addition of PGC1 alpha obviously ameliorated secretion of pro-inflammatory mediators tumor necrosis factor-alpha and Interleukin 6 as well as MCP-1 expression triggered by LPS stimulation, accompanied with reduced infiltration of inflammatory cells. Meanwhile, introduction of PGC1 alpha strongly diminished the expression of cyclooxygenase-2 and inducible nitric oxide synthase as well as their products PGE2 and NO. In addition, administering PGC1 alpha also dramatically alleviated LPS-triggered oxidative stress, as reflected by a reduction of ROS production, and also reduced malondialdehyde and O-2 content, concomitant with enhancement of superoxide dismutase, catalase, and glutathione peroxidase. Similarly, PGC1 alpha effectively ameliorated LPS-induced inflammation response and oxidative stress, as exemplified by reduced pro-inflammatory cytokines and ROS production in LPS-induced RAW264.7 macrophages. Interestingly, PGC1 alpha modulated the expression of HSF1 and the transcriptional activity of X-linked inhibitor of apoptosis (XIAP)-associated factor 1, whereas silencing of HSF1 abolished these effects. More importantly, deletion of HSF1 impeded the anti-inflammatory and anti-oxidant effects of PGC1 alpha in LPS-induced macrophages. Taken together, PGC1 alpha/HSF1 axis have an anti-oxidant and anti-inflammatory effects, indicating that PGC1 alpha/HSF1 may protect against LPS-induced ALI, and thus may be a promising therapy to treat ALI.