Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
Br J Pharmacol. 2024 Nov;181(22):4610-4627. doi: 10.1111/bph.16511. Epub 2024 Aug 8.
Fibrotic lung remodelling after a respiratory viral infection represents a debilitating clinical sequela. Studying or managing viral-fibrotic sequela remains challenging, due to limited therapeutic options and lack of understanding of mechanisms. This study determined whether protein disulfide isomerase A3 (PDIA3) and secreted phosphoprotein 1 (SPP1), which are associated with pulmonary fibrosis, can promote influenza-induced lung fibrotic remodelling and whether inhibition of PDIA3 or SPP1 can resolve viral-mediated fibrotic remodelling.
A retrospective analysis of TriNetX data sets was conducted. Serum from healthy controls and influenza A virus (IAV)-infected patients was analysed. An inhibitor of PDIA3, punicalagin, and a neutralizing antibody for SPP1 were administered in mice. Macrophage cells treated with macrophage colony-stimulating factor (M-CSF) were used as a cell culture model.
The TriNetX data set showed an increase in lung fibrosis and decline in lung function in flu-infected acute respiratory distress syndrome (ARDS) patients compared with non-ARDS patients. Serum samples revealed a significant increase in SPP1 and PDIA3 in influenza-infected patients. Lung PDIA3 and SPP1 expression increased following viral infection in mouse models. Punicalagin administration 2 weeks after IAV infection in mice caused a significant decrease in lung fibrosis and improved oxygen saturation. Administration of neutralizing SPP1 antibody decreased lung fibrosis. Inhibition of PDIA3 decreased SPP1secretion from macrophages, in association with diminished disulfide bonds in SPP1.
The PDIA3-SPP1 axis promotes post-influenza lung fibrosis in mice and that pharmacological inhibition of PDIA3 or SPP1 can treat virus-induced lung fibrotic sequela.
呼吸道病毒感染后的肺纤维化重塑是一种使人虚弱的临床后遗症。由于治疗选择有限且对发病机制缺乏了解，研究或管理病毒性-纤维化后遗症仍然具有挑战性。本研究旨在确定与肺纤维化相关的蛋白二硫键异构酶 A3（PDIA3）和分泌型磷蛋白 1（SPP1）是否可以促进流感引起的肺纤维化重塑，以及抑制 PDIA3 或 SPP1 是否可以解决病毒介导的纤维化重塑。
对 TriNetX 数据集进行了回顾性分析。分析了健康对照者和甲型流感病毒（IAV）感染患者的血清。在小鼠中给予 PDIA3 抑制剂 punicalagin 和 SPP1 的中和抗体。用巨噬细胞集落刺激因子（M-CSF）处理的巨噬细胞用作细胞培养模型。
TriNetX 数据集显示，与非 ARDS 患者相比，流感感染的急性呼吸窘迫综合征（ARDS）患者的肺纤维化增加，肺功能下降。血清样本显示流感感染患者的 SPP1 和 PDIA3 明显增加。在小鼠模型中，病毒感染后肺 PDIA3 和 SPP1 表达增加。在 IAV 感染后 2 周给予 punicalagin 治疗可显著减少肺纤维化并提高氧饱和度。中和 SPP1 抗体可减少肺纤维化。抑制 PDIA3 可减少巨噬细胞中 SPP1 的分泌，同时 SPP1 中的二硫键减少。
PDIA3-SPP1 轴促进了流感后小鼠的肺纤维化，并且药理学抑制 PDIA3 或 SPP1 可以治疗病毒引起的肺纤维化后遗症。
