Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
Department of Pulmonary, Critical Care Medicine, Larner College of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA.
Thorax. 2022 Jul;77(7):669-678. doi: 10.1136/thoraxjnl-2021-216882. Epub 2021 Aug 16.
The role of club cells in the pathology of idiopathic pulmonary fibrosis (IPF) is not well understood. Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum-based redox chaperone required for the functions of various fibrosis-related proteins; however, the mechanisms of action of PDIA3 in pulmonary fibrosis are not fully elucidated.
To examine the role of club cells and PDIA3 in the pathology of pulmonary fibrosis and the therapeutic potential of inhibition of PDIA3 in lung fibrosis.
Role of PDIA3 and aberrant club cells in lung fibrosis was studied by analyses of human transcriptome dataset from Lung Genomics Research Consortium, other public resources, the specific deletion or inhibition of PDIA3 in club cells and blocking SPP1 downstream of PDIA3 in mice.
and club cell secretory protein () signatures are upregulated in IPF compared with control patients. or increases also correlate with a decrease in lung function in patients with IPF. The bleomycin (BLM) model of lung fibrosis showed increases in PDIA3 in SCGB1A1 cells in the lung parenchyma. Ablation of , specifically in SCGB1A1 cells, decreases parenchymal SCGB1A1 cells along with fibrosis in mice. The administration of a PDI inhibitor LOC14 reversed the BLM-induced parenchymal SCGB1A1 cells and fibrosis in mice. Evaluation of PDIA3 partners revealed that SPP1 is a major interactor in fibrosis. Blocking SPP1 attenuated the development of lung fibrosis in mice.
Our study reveals a new relationship with distally localised club cells, PDIA3 and SPP1 in lung fibrosis and inhibition of PDIA3 or SPP1 attenuates lung fibrosis.
细胞球在特发性肺纤维化（IPF）的病理学中的作用尚不清楚。蛋白二硫键异构酶 A3（PDIA3）是一种内质网基础的氧化还原伴侣，是各种纤维化相关蛋白功能所必需的；然而，PDIA3 在肺纤维化中的作用机制尚未完全阐明。
研究细胞球和 PDIA3 在肺纤维化病理学中的作用，以及抑制 PDIA3 在肺纤维化中的治疗潜力。
通过分析肺基因组研究联盟的人类转录组数据集、其他公共资源、细胞球中 PDIA3 的特异性缺失或抑制以及 PDIA3 下游 SPP1 的阻断，研究 PDIA3 和异常细胞球在肺纤维化中的作用。
与对照患者相比，IPF 中 PDIA3 和细胞球分泌蛋白（）的特征上调。或增加也与 IPF 患者肺功能下降相关。博莱霉素（BLM）肺纤维化模型显示肺实质中 SCGB1A1 细胞中的 PDIA3 增加。特异性在 SCGB1A1 细胞中敲除，可减少小鼠肺实质中的 SCGB1A1 细胞和纤维化。PDI 抑制剂 LOC14 的给药逆转了 BLM 诱导的小鼠肺实质 SCGB1A1 细胞和纤维化。对 PDIA3 伴侣的评估表明，SPP1 是纤维化的主要相互作用因子。阻断 SPP1 可减轻小鼠肺纤维化的发展。
我们的研究揭示了肺纤维化中远端细胞球、PDIA3 和 SPP1 之间的新关系，抑制 PDIA3 或 SPP1 可减轻肺纤维化。
