Pirfenidone ameliorates early pulmonary fibrosis in LPS-induced acute respiratory distress syndrome by inhibiting endothelial-to-mesenchymal transition via the Hedgehog signaling pathway.

Pulmonary vascular endothelial dysfunction is a key pathogenic mechanism in acute respiratory distress syndrome (ARDS), resulting in fibrosis in lung tissues, including in the context of COVID-19. Pirfenidone (PFD) has become a novel therapeutic agent for treating idiopathic pulmonary fibrosis (IPF) and can improve lung function, inhibit fibrosis and inhibit inflammation. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play a crucial role in various respiratory diseases. However, the role of PFD in the course of EndMT in LPS-induced ARDS remains poorly understood. The purpose of this study was to explore the anti-EndMT effects of PFD on pulmonary fibrosis after LPS-induced ARDS. First, we determined that PFD significantly reduced LPS-induced ARDS, as shown by significant pathological alterations, and alleviated the oxidative stress and inflammatory response in vitro and in vivo. Furthermore, PFD decreased pulmonary fibrosis in LPS-induced ARDS by inhibiting EndMT and reduced the expression levels of Hedgehog (HH) pathway target genes, such as Gli1 and α-SMA, after LPS induction. In summary, this study confirmed that inhibiting the HH pathway by PFD could decrease pulmonary fibrosis by downregulating EndMT in LPS-induced ARDS. In conclusion, we demonstrate that PFD is a promising agent to attenuate pulmonary fibrosis following ARDS in the future.

Hepcidin Alleviates LPS-Induced ARDS by Regulating the Ferritin-Mediated Suppression of Ferroptosis.

ABSTRACT: The effects of ferroptosis, an iron-dependent cell death, on acute respiratory distress syndrome (ARDS) remain largely elusive. Hepcidin, encoded by the HAMP gene, affects inflammation, and iron homeostasis. The present study aimed to investigate whether hepcidin protects against ferroptosis in lipopolysaccharide (LPS)-induced ARDS. Our results confirmed that ferroptosis aggravated lung inflammation and damage in LPS-induced ARDS. Hepcidin defended against ferroptosis, with results similar to those of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, hepcidin decreased iron uptake, as determined by Transferrin Receptor 1 (TfR1) expression levels, and increased iron storage, based on ferritin heavy chain (FTH) expression. The effects of hepcidin on the A549 cell line were in line with the in vivo results. In addition, we used si-FTH to knock down FTH expression and found that this suppressed the ability of hepcidin to protect against ferroptosis. Collectively, our data suggest that hepcidin inhibits ferroptosis by increasing FTH expression in LPS-induced ARDS; thus, hepcidin may represent a possible treatment targeting ferroptosis.