Revealing the Pathogenic and Aging-related Mechanisms of the Enigmatic Idiopathic Pulmonary Fibrosis. An Integral Model

A growing body of evidence indicates that aberrant activation of alveolar epithelial cells and fibroblasts in an aging lung plays a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the biopathological processes linking aging with IPF and the mechanisms responsible for the abnormal activation of epithelial cells and fibroblasts have not been elucidated. Many of the telomere(definition) attrition, cellular senescence(definition))." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">hallmarks of aging(definition) (e.g., genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction(definition), and cellular senescence) have been proposed as essential mechanisms for the development of IPF; however, these disturbances are not restricted to IPF and also occur in other aging-related lung disorders, primarily chronic obstructive pulmonary disease (COPD). Therefore, an unanswered question is why a current/former smoker of about 60 years of age with shorter telomeres, alveolar epithelial senescence, excessive oxidative stress, and mitochondrial dysfunction develops IPF and not COPD; in other words, what makes old lungs specifically susceptible to develop IPF? In this Perspective, we propose an integral model in which the combination of some gene variants and/or gene expression in the aging lung results in the loss of epithelial integrity and consequently in the failure of the alveoli to correctly respond to injury and to face the stress associated with mechanical stretch. Afterward, a distinctive epigenetic "reprogramming" that affects both epithelial cells and fibroblasts provokes, among others, the recapitulation of developmental pathways and the aberrant activation and miscommunication between both cell types, resulting in the exaggerated production and accumulation of extracellular matrix and the subsequent destruction of the lung architecture.