Date Published: August 26, 2016
Publisher: John Wiley and Sons Inc.
Author(s): Yair Romero, Marta Bueno, Remedios Ramirez, Diana Álvarez, John C. Sembrat, Elena A. Goncharova, Mauricio Rojas, Moisés Selman, Ana L. Mora, Annie Pardo.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal disease associated with aging. However, the molecular mechanisms of the aging process that contribute to the pathogenesis of IPF have not been elucidated. IPF is characterized by abundant foci of highly active fibroblasts and myofibroblasts resistant to apoptosis. Remarkably, the role of aging in the autophagy activity of lung fibroblasts and its relationship with apoptosis, as adaptive responses, has not been evaluated previously in this disease. In the present study, we analyzed the dynamics of autophagy in primary lung fibroblasts from IPF compared to young and age‐matched normal lung fibroblasts. Our results showed that aging contributes for a lower induction of autophagy on basal conditions and under starvation which is mediated by mTOR pathway activation. Treatment with rapamycin and PP242, that target the PI3K/AKT/mTOR signaling pathway, modified starvation‐induced autophagy and apoptosis in IPF fibroblasts. Interestingly, we found a persistent activation of this pathway under starvation that contributes to the apoptosis resistance in IPF fibroblasts. These findings indicate that aging affects adaptive responses to stress decreasing autophagy through activation of mTORC1 in lung fibroblasts. The activation of this pathway also contributes to the resistance to cell death in IPF lung fibroblasts.
Idiopathic pulmonary fibrosis (IPF) is a highly lethal lung disease of unknown etiology characterized by activation of alveolar epithelial cells, fibroblast/myofibroblast proliferation, and activation with exacerbated deposit of extracellular matrix (ECM) resulting in the gradual destruction of the lung architecture (Selman et al., 2001; King et al., 2011). In this sequence of pathological events, fibroblasts/myofibroblasts are usually organized in a distinctive foci and it has been suggested to be resistant to apoptosis (Kazufumi et al., 1997).
Aging is not a disease itself, but the biological processes that change with age have a crucial role in numerous chronic degenerative diseases (Kennedy et al., 2014). One common feature in age‐related diseases such as cancer, cardiovascular disorders, and neurodegenerative diseases is autophagy dysfunction (Rubinsztein et al., 2012; He et al., 2013). Moreover, there is growing evidence supporting that autophagy deficiency recapitulates aging phenotype (Cuervo et al., 2005; Rubinsztein et al., 2011).
The present study was supported by PAPIIT IN214612‐3, CONACYT 251636, NIH RHL131789A, and NIH R01 HL123766‐01A1 and by Vascular Medicine Institute, University of Pittsburgh, the Institute for Transfusion Medicine, and the Hemophilia Center of Western Pennsylvania.
All authors participated in the revision of the manuscript. YR, ALM, and AP performed study conception and design; YR, RR, DA, and JS carried out acquisition of data; YR, MB, EAG, MR, MS, ALM, and AP carried out analysis and interpretation of data; YR, MR, MS, ALM, and AP drafted the manuscript.