title: Insufficient autophagy in idiopathic pulmonary fibrosis.
abstract: Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation, and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type-specific manner and is a promising clue for understanding the pathogenesis of IPF.
authors.affiliation: Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. araya@jikei.ac.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Araya
authors.forename: Jun
authors.initials: J
authors.lastname: Kojima
authors.forename: Naoki
authors.initials: N
authors.lastname: Takasaka
authors.forename: Saburo
authors.initials: S
authors.lastname: Ito
authors.forename: Satoko
authors.initials: S
authors.lastname: Fujii
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hara
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yanagisawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Chikako
authors.initials: C
authors.lastname: Tsurushige
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawaishi
authors.forename: Noriki
authors.initials: N
authors.lastname: Kamiya
authors.forename: Jun
authors.initials: J
authors.lastname: Hirano
authors.forename: Makoto
authors.initials: M
authors.lastname: Odaka
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Morikawa
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kawabata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hano
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kuwano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D001343:Autophagy; D002454:Cell Differentiation / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000503:physiopathology*; D058628:Myofibroblasts / Q000166:cytology; D000071456:Sequestosome-1 Protein; D014415:Tunicamycin / Q000494:pharmacology; D025801:Ubiquitin / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D014415:Tunicamycin