Martín-Vicente Paula, López-Martínez Cecilia, López-Alonso Inés, Exojo-Ramírez Sara M, Duarte-Herrera Israel David, Amado-Rodríguez Laura, Ordoñez Irene, Cuesta-Llavona Elias, Gómez Juan, Campo Natalia, O'Kane Cecilia M, McAuley Daniel F, Huidobro Covadonga, Albaiceta Guillermo M
Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.
Instituto Universitario de Oncología del Principado de Asturias.
Am J Respir Cell Mol Biol. 2025 Feb;72(2):195-205. doi: 10.1165/rcmb.2023-0449OC.
Severe lung injury requiring mechanical ventilation may lead to secondary fibrosis. Senescence, a cell response characterized by cell cycle arrest and a shift toward a proinflammatory/profibrotic phenotype, is one of the involved mechanisms. In this study, we explore the contribution of mechanical stretch as a trigger of senescence of the respiratory epithelium and its link with fibrosis. Human lung epithelial cells and fibroblasts were exposed to mechanical stretch, and senescence was assessed. In addition, fibroblasts were exposed to culture media preconditioned by senescent epithelial cells, and their activation was studied. Transcriptomic profiles from stretched, senescent epithelial cells and activated fibroblasts were combined to identify potential activated pathways. Finally, the senolytic effects of digoxin were tested in these models. Mechanical stretch induced senescence in lung epithelial cells, but not in fibroblasts. This stretch-induced senescence has specific features compared with senescence induced by doxorubicin. Fibroblasts were activated after exposure to supernatants conditioned by epithelial senescent cells. Transcriptomic analyses revealed Notch signaling as potentially responsible for the epithelial-mesenchymal cross-talk, because blockade of this pathway inhibits fibroblast activation. Treatment with digoxin reduced the percentage of senescent cells after stretch and ameliorated the fibroblast response to preconditioned media. These results suggest that lung fibrosis in response to mechanical stretch may be caused by the paracrine effects of senescent cells. This pathogenetic mechanism can be pharmacologically manipulated to improve lung repair.
需要机械通气的严重肺损伤可能会导致继发性纤维化。衰老作为一种以细胞周期停滞和向促炎/促纤维化表型转变为特征的细胞反应，是其中一种相关机制。在本研究中，我们探讨了机械牵张作为呼吸道上皮细胞衰老触发因素的作用及其与纤维化的联系。将人肺上皮细胞和成纤维细胞暴露于机械牵张下，并评估细胞衰老情况。此外，将成纤维细胞暴露于经衰老上皮细胞预处理的培养基中，并研究其激活情况。结合拉伸后衰老上皮细胞和激活的成纤维细胞的转录组图谱，以确定潜在的激活途径。最后，在这些模型中测试了地高辛的溶衰老作用。机械牵张诱导肺上皮细胞衰老，但不诱导成纤维细胞衰老。与阿霉素诱导的衰老相比，这种牵张诱导的衰老具有特定特征。成纤维细胞在暴露于上皮衰老细胞预处理的上清液后被激活。转录组分析显示Notch信号可能是上皮-间质相互作用的原因，因为阻断该途径可抑制成纤维细胞激活。地高辛治疗可降低牵张后衰老细胞的百分比，并改善成纤维细胞对预处理培养基的反应。这些结果表明，对机械牵张的肺纤维化反应可能是由衰老细胞的旁分泌作用引起的。这种发病机制可以通过药理学手段进行调控，以改善肺修复。
