Background 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. Objectives 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. Methods 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. Results PDIA3 and club cell secretory protein ( SCGB1A1 ) signatures are upregulated in IPF compared with control patients. PDIA3 or SCGB1A1 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 Pdia3 , 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. Conclusions 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. All the primary data are available from the authors upon request. Human data are available in the public databases that are documented in the manuscript.

中文翻译：

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抑制 club 细胞中的 PDIA3 可减弱骨桥蛋白的产生和肺纤维化

背景 俱乐部细胞在特发性肺纤维化 (IPF) 病理学中的作用尚不清楚。蛋白二硫键异构酶 A3 (PDIA3)，一种基于内质网的氧化还原伴侣，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。目的 探讨俱乐部细胞和 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。方法 通过分析来自肺基因组学研究联盟的人类转录组数据集、其他公共资源、特异性缺失或抑制 club 细胞中的 PDIA3 以及阻断小鼠 PDIA3 下游的 SPP1，研究 PDIA3 和异常的 club 细胞在肺纤维化中的作用。结果 与对照患者相比，IPF 中的 PDIA3 和俱乐部细胞分泌蛋白 (SCGB1A1) 特征上调。PDIA3 或 SCGB1A1 增加也与 IPF 患者肺功能下降相关。肺纤维化的博来霉素 (BLM) 模型显示肺实质中 SCGB1A1 细胞的 PDIA3 增加。Pdia3 的消融，特别是在 SCGB1A1 细胞中，减少了小鼠的实质 SCGB1A1 细胞以及纤维化。PDI 抑制剂 LOC14 的给药逆转了 BLM 诱导的小鼠实质 SCGB1A1 细胞和纤维化。对 PDIA3 合作伙伴的评估表明，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。结论我们的研究揭示了与远端局限性俱乐部细胞的新关系，肺纤维化中的 PDIA3 和 SPP1 以及 PDIA3 或 SPP1 的抑制可减轻肺纤维化。所有主要数据均可根据要求从作者处获得。手稿中记录的公共数据库中提供了人类数据。