| Autor: |
Martín-Vicente P; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.; Universidad de Oviedo, Oviedo, Asturias, Spain., López-Martínez C; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain., López-Alonso I; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.; Centro de Investigación Biomédica en Red, Enfermedades Respiratorias, Madrid, Spain., Exojo-Ramírez SM; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain., Duarte-Herrera ID; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain., Amado-Rodríguez L; Hospital Universitario Central de Asturias, Cardiac Intensive Care Unit, Oviedo, Spain.; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.; Centro de Investigación Biomédica en Red, Enfermedades Respiratorias, Madrid, Spain., Ordoñez I; Universidad de Oviedo, Oviedo, Asturias, Spain., Cuesta-Llavona E; Hospital Universitario Central de Asturias, Genetics, Oviedo, Spain., Gómez J; Hospital Universitario Central de Asturias, Genetics, Oviedo, Spain., Campo N; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain., O'Kane CM; Queen's University of Belfast, Centre for Infection and Immunity, Belfast, N. Ireland, United Kingdom of Great Britain and Northern Ireland.; United Kingdom of Great Britain and Northern Ireland., McAuley DF; University of Belfast, Belfast, United Kingdom of Great Britain and Northern Ireland., Huidobro C; Universidad de Oviedo, Oviedo, Asturias, Spain., Albaiceta GM; Hospital Universitario Central de Asturias, Department of Functional Biology, Oviedo, Asturias, Spain; gma@crit-lab.org. |
| Abstrakt: |
Severe lung injury requiring mechanical ventilation may lead to secondary fibrosis. Senescence, a cell response characterized by cell cycle arrest and a shift towards a proinflammatory/profibrotic phenotype, is one of the involved mechanisms. Here, we explore the contribution of mechanical stretch as trigger of senescence of the respiratory epithelium and its link with fibrosis. Human lung epithelial cells and fibroblasts were exposed in vitro to mechanical stretch, and senescence 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 to senescence induced by doxorubicin. Fibroblasts were activated after exposure to supernatants conditioned by epithelial senescent cells. Transcriptomic analyses revealed notch signaling as a potential responsible for the epithelial-mesenchymal crosstalk, as 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. |
