PDF(Pubmed)
Abstract：
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.
摘要：
衰老是慢性肺疾病（CLDs）的主要危险因素，包括特发性肺纤维化（IPF）和慢性阻塞性肺疾病（COPD）。因此，在这些患者中，不同类型的肺细胞，包括成纤维细胞，衰老的标志如细胞衰老增加。然而,关于在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,我们表征了来自对照的原代人肺成纤维细胞（phLF）的衰老，IPF,或COPD患者在基线和暴露于疾病相关损伤后（H2O2，博来霉素，TGF-β1）并研究了它们在肺类器官模型中支持祖细胞潜能的能力。Bulk-RNA测序显示，来自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和博来霉素而不是TGF-β1诱导不同疾病起源的phLF衰老。暴露于不同的触发因素导致以不同的SASP概况为特征的phLF的不同衰老程序。最后,与博来霉素和H2O2处理的phLF共培养降低了肺泡上皮祖细胞的祖细胞潜能。总之,来自COPD和IPF的phLF共享保守的衰老反应,其根据损伤而变化,并损害离体的肺泡上皮祖细胞能力。
