CSE Induces Lung Epithelial Cell-derived Exosomal LINC01133-mediated FOXA1 Activity Through SRSF6 to Affect MRC-5 Cellular Lipid Metabolism and Autophagy.

Smoking is an important risk factor for the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoke (CS) damages alveolar epithelial cells and induces them to release exosomes (Exos). Although exosomal LINC01133 has been shown to regulate epithelial–mesenchymal transition (EMT), its effect and mechanism of action in IPF remain unclear. The present study aimed to investigate the effect and molecular mechanism of exosomal LINC01133 in IPF. Bleomycin (BLM) was injected into the trachea of mice to establish an IPF animal model, and the mice were treated with CS or Exos. In addition, 5% cigarette smoke extract (CSE) was added to the culture medium of type II alveolar epithelial cells (AT2) to induce the secretion of Exos. Western blot and RT–qPCR analyses were performed to detect the expression of related proteins or genes, and a CCK-8 assay, immunofluorescence staining, MDC staining, HE staining, and Masson’s staining were conducted to evaluate MRC-5 cell activation and mouse lung tissue fibrosis. The result shows that CSE-induced AT2 cells secreted exosomal LINC01133, which promoted the expression of α-SMA and lipid metabolism-related markers (DGAT2, MTP, FATP2, ACAT2, GPAT1, and APOB) in MRC-5 cells in vitro. Exosomal LINC01133 decreased the expression of autophagy-related proteins (ATG7, Beclin1, and LC3Ⅱ/I) and resulted in abnormal activation of MRC-5 cells. Exosomal LINC01133 also promoted lipid accumulation and inhibited autophagy in lung fibroblasts in vivo. Mechanistically, exosomal LINC01133 inhibited FOXA1/UCP1 signaling by upregulating SRSF6 expression, which promoted lipid accumulation and inhibited autophagy, ultimately activating lung fibroblasts and accelerating the progression of IPF in mice. Overall, CSE-induced AT2 cell-derived exosomal LINC01133 promotes the activation of lung fibroblasts and accelerates the progression of IPF.