LCN2-positive alveolar type II cells promote silica-induced pulmonary fibrosis via STAT3-TGF-β1-Smad3-mediated signaling

Abstract

Lipocalin-2 (LCN2), an innate immune protein, has been identified as a potential biomarker in a range of inflammatory and fibrotic lung diseases. Nevertheless, its specific role and the underlying mechanisms in silica-induced pulmonary fibrosis remain unclear. This study found a significant increase in LCN2 expression in the lung tissues of silica-exposed mice during the stage of inflammation and fibrosis. The increased LCN2 was primarily derived from alveolar type II epithelial cells (AT2 cells). We further generated LCN2-overexpressing mouse AT2 cells (LCN2-OE AT2 cells) in vitro. These LCN2-OE AT2 cells exhibited significant upregulation of TGF-β1 and activation of Smad3, promoting the epithelial-mesenchymal transition (EMT) process. Additionally, exposure to silica in vitro led to an increase in the TGF-β1-Smad3 pathway and EMT process in AT2 cells. However, this response was effectively decreased when combined with an LCN2 inhibitor. Our findings highlight the significance of LCN2 originating from AT2 cells in both EMT and silica-induced pulmonary fibrosis, indicating a potential new treatment strategy for pulmonary fibrosis targeting LCN2.