College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China.
State Key Laboratory of Cell Differentiation and Regulation, Xinxiang, Henan, China.
Respir Res. 2024 Nov 9;25(1):401. doi: 10.1186/s12931-024-03016-5.
Pulmonary fibrosis (PF) is a chronic, progressive lung disease characterized by fibroblast proliferation, extensive extracellular matrix and collagen deposition, accompanied by inflammatory damage, ultimately leading to death due to respiratory failure. 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 need further elucidation. In this paper, pulmonary 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 promote ER stress response and apoptosis. Mechanically, lactate activated Caspase-12 via ATF4-Chop axis to induce cell apoptosis and promote fibrosis. ER stress inhibitor could effectively suppress alveolar epithelial cells apoptosis and pulmonary 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.
肺纤维化（PF）是一种慢性、进行性肺部疾病，其特征是成纤维细胞增殖、细胞外基质和胶原广泛沉积，并伴有炎症损伤，最终导致呼吸衰竭死亡。肺纤维化组织中的内质网（ER）应激确实被认为是加重 PF 发展的重要因素。新出现的证据表明，乳酸引起的 ER 应激与 PF 中的细胞凋亡之间存在潜在关联。然而，这一过程中的机制仍需要进一步阐明。在本研究中，通过气管内滴注博来霉素（BLM）诱导小鼠肺纤维化模型。在细胞模型中，用乳酸和 TGF-β处理 II 型上皮细胞，以检测 ER 应激和细胞凋亡标志物。乳酸可促进 ER 应激反应和细胞凋亡。机制上，乳酸通过 ATF4-Chop 轴激活 Caspase-12 诱导细胞凋亡和促进纤维化。ER 应激抑制剂可有效抑制肺泡上皮细胞凋亡和肺纤维化。综上所述，乳酸的促纤维化特性与 ER 应激引起的肺泡上皮细胞凋亡有关，为肺纤维化提供了新的潜在治疗靶点。
