衰老是慢性肺病（CLD）的主要危险因素，包括特发性肺纤维化（IPF）和慢性阻塞性肺病（COPD）。因此，这些患者的不同肺细胞类型（包括成纤维细胞）中的细胞衰老等衰老标志有所增加。然而，人们对不同疾病背景下诱导衰老表型的不同触发因素及其在 CLD 发病机制中的作用知之甚少。因此，我们对来自对照、IPF 或 COPD 患者的原代人肺成纤维细胞 (phLF) 的衰老进行了表征，包括基线时和暴露于疾病相关损伤（H2O2、博莱霉素、TGF-β1）后，并研究了它们支持祖细胞潜力的能力。肺类器官模型。大量 RNA 测序显示，IPF 和 COPD 的 phLF 激活不同的转录程序，但在基线时具有相似的衰老表型。此外，H2O2 和博莱霉素（而非 TGF-β1）可诱导不同疾病来源的 phLF 衰老。暴露于不同的触发因素会导致 phLF 出现不同的衰老程序，其特征是不同的 SASP 谱。最后，与博莱霉素和 H2O2 处理的 phLF 共培养降低了肺泡上皮祖细胞的祖细胞潜力。总之，来自 COPD 和 IPF 的 phLF 具有保守的衰老反应，该反应根据损伤而变化，并损害离体肺泡上皮祖细胞的能力。

Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging like cellular senescence are increased in these patients in different lung cell types including fibroblasts. However, little is known about the different triggers that induce a senescence phenotype in different disease backgrounds and its role in CLD pathogenesis. Therefore, we characterized senescence in primary human lung fibroblasts (phLF) from control, IPF, or COPD patients at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, TGF-β1) and studied their capacity to support progenitor cell potential in a lung organoid model. Bulk-RNA sequencing revealed that phLF from IPF and COPD activate different transcriptional programs but share a similar senescence phenotype at baseline. Moreover, H2O2 and bleomycin but not TGF-β1 induced senescence in phLF from different disease origins. Exposure to different triggers resulted in distinct senescence programs in phLF characterized by different SASP profiles. Finally, co-culture with bleomycin- and H2O2-treated phLF reduced the progenitor cell potential of alveolar epithelial progenitor cells. In conclusion, phLF from COPD and IPF share a conserved senescence response that varies depending on the insult and impairs alveolar epithelial progenitor capacity ex vivo.