title: Age-driven developmental drift in the pathogenesis of idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal disease of unknown aetiology. A growing body of evidence supports that IPF represents an epithelial-driven process characterised by aberrant epithelial cell behaviour, fibroblast/myofibroblast activation and excessive accumulation of extracellular matrix with the subsequent destruction of the lung architecture. The mechanisms involved in the abnormal hyper-activation of the epithelium are unclear, but we propose that recapitulation of pathways and processes critical to embryological development associated with a tissue specific age-related stochastic epigenetic drift may be implicated. These pathways may also contribute to the distinctive behaviour of IPF fibroblasts. Genomic and epigenomic studies have revealed that wingless/Int, sonic hedgehog and other developmental signalling pathways are reactivated and deregulated in IPF. Moreover, some of these pathways cross-talk with transforming growth factor-β activating a profibrotic feedback loop. The expression pattern of microRNAs is also dysregulated in IPF and exhibits a similar expression profile to embryonic lungs. In addition, senescence, a process usually associated with ageing, which occurs early in alveolar epithelial cells of IPF lungs, likely represents a conserved programmed developmental mechanism. Here, we review the major developmental pathways that get twisted in IPF, and discuss the connection with ageing and potential therapeutic approaches.
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico city, Mexico mselmanl@yahoo.com.mx.
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico city, Mexico.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
mesh_terms: D000368:Aged; D000375:Aging; D000818:Animals; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology*; D040961:Genetic Drift; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000503:physiopathology*; D008168:Lung / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D058628:Myofibroblasts / Q000473:pathology*; D015398:Signal Transduction; D013269:Stochastic Processes; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs