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Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGF β1
Author(s) -
Sosulski Meredith L.,
Gongora Rafael,
Danchuk Svitlana,
Dong Chunmin,
Luo Fayong,
Sanchez Cecilia G.
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12357
Subject(s) - mitophagy , pulmonary fibrosis , autophagy , pink1 , idiopathic pulmonary fibrosis , biology , fibrosis , cancer research , transforming growth factor , lung , immunology , microbiology and biotechnology , pathology , medicine , apoptosis , biochemistry
Summary Aging constitutes a significant risk factor for fibrosis, and idiopathic pulmonary fibrosis ( IPF ) is characteristically associated with advancing age. We propose that age‐dependent defects in the quality of protein and cellular organelle catabolism may be causally related to pulmonary fibrosis. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle‐aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy (mitophagy). Fibroblast to myofibroblast differentiation ( FMD ) is an important feature of pulmonary fibrosis in which the profibrotic cytokine TGF β1 plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts’ fate. On the contrary, FMD mediated by TGF β1 is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK 1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a TGF β1‐adenoviral model of lung fibrosis. PINK 1 expression is also reduced in the aging murine lung and biopsies from IPF patients compared to controls. Furthermore, deficient PINK 1 promotes a profibrotic environment. Collectively, this study indicates that an age‐related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of pulmonary fibrosis. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age‐related fibrotic diseases.

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