title: mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts.
abstract: 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.
authors: Facultad de Ciencias, Universidad Nacional Autónoma de México, Av Universidad 3000, México, DF, CP 04510, México.
authors: Yair
authors: Y
authors: Romero
authors: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.|Vascular Medicine Institute, Pulmonary Division, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.
authors: Marta
authors: M
authors: Bueno
authors: Facultad de Ciencias, Universidad Nacional Autónoma de México, Av Universidad 3000, México, DF, CP 04510, México.
authors: Remedios
authors: R
authors: Ramirez
authors: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.
authors: Diana
authors: D
authors: Álvarez
authors: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.
authors: John C
authors: JC
authors: Sembrat
authors: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.|Vascular Medicine Institute, Pulmonary Division, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.
authors: Elena A
authors: EA
authors: Goncharova
authors: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.
authors: Mauricio
authors: M
authors: Rojas
authors: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, México, Tlalpan 4502, DF, CP 14080, México.
authors: Moisés
authors: M
authors: Selman
authors: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.|Vascular Medicine Institute, Pulmonary Division, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15261, USA.
authors: Ana L
authors: AL
authors: Mora
authors: Facultad de Ciencias, Universidad Nacional Autónoma de México, Av Universidad 3000, México, DF, CP 04510, México.
authors: Annie
authors: A
authors: Pardo
keywords: aging; apoptosis; autophagy; idiopathic pulmonary fibrosis; lung fibroblast; mTOR pathway