ERRα protects against sepsis-induced acute lung injury in rats

Abstract Sepsis-induced acute lung injury (ALI) is associated with poor survival rates. The identification of potential therapeutic targets for preventing sepsis-induced ALI has clinical importance. Here, we show that estrogen-related receptor alpha (ERRα) protects against sepsis-induced ALI through ERRα-mediated apoptosis and autophagy. ERRα was upregulated in inflammation models from lipopolysaccharides (LPS)-treated rat pulmonary microvascular endothelial cells (PMVECs) and cecal ligation and puncture (CLP)-induced septic rats. In vitro , overexpression of ERRα ameliorated LPS-induced degradation of adherens junctional molecules, upregulation of bax, cleaved caspase 3 and cleaved caspase 9 levels and downregulation of anti-apoptotic protein Bcl-2 level, and promoted the formation of autophagic flux, while the knockdown of ERRα exacerbated LPS-induced apoptosis and inhibited the activation of autophagy. Rats injected with ERRα agonist were subjected to CLP to elucidate the role of ERRα in sepsis-induced ALI in vivo . Administration of ERRα agonist alleviated the pathological damage of lung tissue, increased the levels of tight junction proteins and adherens junction proteins, and decreased the expression of apoptosis-related proteins. Promoting the expression of ERRα significantly enhanced the process of autophagy and reduced CLP-induced ALI. Mechanistically, ERRα is essential to regulate the balance between autophagy and apoptosis to maintain the adherens junctional integrity. These findings indicate that activation of ERRα provides a new therapeutic opportunity to prevent sepsis-induced ALI.