Pulmonary fibrosis (PF) is a lethal lung disease that predominantly affects older adults; however, whether and how aging triggers fibrosis remains unclear. To pinpoint the predominant initiating factors of PF, we first analyzed single-cell RNA sequencing (scRNA-seq) data from the lung tissues of 45 normal donors and 51 PF patients and found that aging might serve as the primary catalyst for PF development. To further investigate the influence of aging on PF formation, we conducted a comprehensive and thorough study employing a natural aging mouse model. We found that dynamic alterations in the quantity and types of collagen fibers during aging-induced PF progression, especially in collagenous (Col) I, emerged as the predominant driver of PF. We then investigated the regulation of Col I synthesis during aging using primary alveolar type 2 (AT2) cells and A549 cells line through conditioned media and Transwell coculture, and found that secretions—particularly plasminogen activator inhibitor (PAI)-1—from aged AT2 cells promoted fibrosis and enhanced collagen type I alpha 1 (Col1al) production via the transforming growth factor (TGF)-β/small mother against decapentaplegic (Smad)2/3 pathway. Furthermore, scRNA-seq and a histological analysis of human lung tissue demonstrated a significant upregulation of SERPINE1 (the gene encoding PAI-1) and PAI-1 expression in both aging lung tissue and AT2 cells, which was consistent with our findings from animal experiments, providing additional evidence for the pivotal role of PAI-1 during aging and the development of PF. Our research demonstrates that PAI-1, a crucial factor secreted by aging AT2 cells, exerts a pivotal role in promoting the synthesis of Col1a1 in fibroblasts, subsequently leading to Col I deposition, and in driving the progression of PF by mediating the TGF-β/Smad2/3 pathway. Our findings offer critical evidence for the involvement of epithelial dysfunction in age-related PF and provides potential novel therapeutic targets for clinical intervention.

中文翻译：

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源自肺泡 2 型细胞的 PAI-1 驱动衰老相关肺纤维化


肺纤维化 （PF） 是一种致命的肺部疾病，主要影响老年人;然而，衰老是否以及如何触发纤维化仍不清楚。为了确定 PF 的主要起始因素，我们首先分析了来自 45 名正常供体和 51 名 PF 患者肺组织的单细胞 RNA 测序 （scRNA-seq） 数据，发现衰老可能是 PF 发展的主要催化剂。为了进一步研究衰老对 PF 形成的影响，我们采用自然衰老小鼠模型进行了一项全面而彻底的研究。我们发现，在衰老诱导的 PF 进展过程中，胶原纤维数量和类型的动态变化，尤其是在胶原 （Col） I 中，成为 PF 的主要驱动因素。然后，我们使用原代肺泡 2 型 （AT2） 细胞和 A549 细胞系通过条件培养基和 Transwell 共培养研究了衰老过程中 Col I 合成的调节，发现来自老年 AT2 细胞的分泌物——特别是纤溶酶原激活物抑制剂 （PAI）-1——通过转化生长因子 （TGF）-β/小母体对抗脱瘫 （Smad）2/3 通路促进纤维化并增强 I 型 α 1 （Col1al） 的产生。此外，scRNA-seq 和人肺组织的组织学分析表明，衰老肺组织和 AT2 细胞中 SERPINE1（编码 PAI-1 的基因）和 PAI-1 表达显着上调，这与我们的动物实验结果一致，为 PAI-1 在衰老和 PF 发展过程中的关键作用提供了更多证据。 我们的研究表明，PAI-1 是衰老 AT2 细胞分泌的关键因子，在促进成纤维细胞中 Col1a1 的合成，随后导致 Col I 沉积，并通过介导 TGF-β/Smad2/3 通路驱动 PF 的进展中起关键作用。我们的研究结果为上皮功能障碍参与年龄相关性 PF 提供了关键证据，并为临床干预提供了潜在的新治疗靶点。