Abstract
Pulmonary Fibrosis (PF) is a chronic, progressive lung disease characterized by fibrous tissue excessive proliferation and enhanced glycolysis level in lung with high lactate level accumulation, which could be triggered by alveolar epithelial cell apoptosis. Endoplasmic reticulum (ER) stress in pulmonary fibrotic tissue is indeed recognized as a significant factor exacerbating PF development. Emerging evidences indicated a potential association between ER stress induced by lactate and cellular apoptosis in PF; However, the mechanisms in this process needs further elucidation. In this paper, lung fibrosis model was induced by bleomycin (BLM) intratracheally in mice. In the cellular model, type II epithelial cells were treated by lactate and TGF-β to detect ER stress and apoptosis markers. Lactate could exacerbate lung fibrosis by facilitating ER stress response and cell apoptosis. Mechanismly, lactate activated Caspase-12 via ATF4-Chop axis to induce cell apoptosis and promoting fibrosis with downregulated Bcl-2 and enhanced Bax. ER stress inhibitor could effectively suppress alveolar epithelial cells apoptosis and lung fibrosis. We concluded that pro-fibrotic properties of lactate are associated with alveolar epithelial cells apoptosis by causing ER stress and thus provide new potential therapeutic targets for pulmonary fibrosis.