The cell fate regulated by autophagy and ER stress in idiopathic pulmonary fibrosis.

• Project/Area Number: 23591162
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Jikei University School of Medicine
• Principal Investigator: ARAYA Jun 東京慈恵会医科大学, 医学部, 准教授 (90468679)
• Co-Investigator(Renkei-kenkyūsha): KUWANO Kazuyoshi 東京慈恵会医科大学, 医学部, 教授 (40205266)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: オートファジー

Research Abstract

Autophagy, a process of lysosomal degradation, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. 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 IPF lungs reveals that epithelial cells show increased cellular senescence. Insufficient autophagy is demonstrated in both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF). 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.

Research Products

• [Journal Article] Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence (2014)
  • Author(s): Takasaka N, Araya J, Hara H, Ito S, Kobayashi K, Kurita Y, Wakui H, Yoshii Y, Yumino Y, Fujii S, Minagawa S, Tsurushige C, Kojima J, Numata T, Shimizu K, Kawaishi M, Kaneko Y, Kamiya N, Hirano J, Odaka M, Morikawa T, Nishimura SL, Nakayama K, Kuwano K.
  • Journal Title: J Immunol Volume: 192(3) Pages: 958-68
  • Peer Reviewed
• [Journal Article] Insufficient autophagy in idiopathic pulmonary fibrosis (2013)
  • Author(s): Araya J, Kojima J, Takasaka N, Ito S, Fujii S, Hara H, Yanagisawa H, Kobayashi K, Tsurushige C, Kawaishi M, Kamiya N, Hirano J, Odaka M, Morikawa T, Nishimura SL, Kawabata Y, Hano H, Nakayama K, Kuwano K.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 304(1)
  • Peer Reviewed
• [Journal Article] Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD (2013)
  • Author(s): Kojima J, Araya J, Hara H, Ito S, Takasaka N, Kobayashi K, Fujii S, Tsurushige C, Numata T, Ishikawa T, Shimizu K, Kawaishi M, Saito K, Kamiya N, Hirano J, Odaka M, Morikawa T, Hano H, Arai S, Miyazaki T, Kaneko Y, Nakayama K, Kuwano K.
  • Journal Title: Respir Res. Volume: 14 Pages: 30-30
  • Peer Reviewed
• [Journal Article] Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence (2013)
  • Author(s): Hara H, Araya J, Ito S, Kobayashi K, Takasaka N, Yoshii Y, Wakui H, Kojima J, Shimizu K, Numata T, Kawaishi M, Kamiya N, Odaka M, Morikawa T, Kaneko Y, Nakayama K, Kuwano K.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 305(10)
  • Peer Reviewed
• [Journal Article] Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence. (2013)
  • Author(s): Hara H, Araya J, Ito S, Kobayashi K, Takasaka N, Yoshii Y, Wakui H, Kojima J, Shimizu K, Numata T, Kawaishi M, Kamiya N, Odaka M, Morikawa T, Kaneko Y, Nakayama K, Kuwano K.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 305(10) Issue: 10 Pages: L737-L746
  • DOI: 10.1152/ajplung.00146.2013
  • Peer Reviewed
• [Journal Article] Autophagy in the pathogenesis of pulmonary disease. (2013)
  • Author(s): Araya J, Hara H, Kuwano K.
  • Journal Title: Intern Med Volume: 52(20) Pages: 2295-303
  • NAID: 130003383668
  • Peer Reviewed
• [Journal Article] Insufficient autophagy in idiopathic pulmonary fibrosis. (2013)
  • Author(s): Araya J, et al.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: Jan 1;304(1): Issue: 1 Pages: L56-L69
  • DOI: 10.1152/ajplung.00213.2012
  • Peer Reviewed
• [Journal Article] Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease (2012)
  • Author(s): Fujii S, Hara H, Araya J, Takasaka N, Kojima J, Ito S, Minagawa S, Yumino Y, Ishikawa T, Numata T, Kawaishi M, Hirano J, Odaka M, Morikawa T, Nishimura SL, Nakayama K, Kuwano K.
  • Journal Title: Oncoimmunology Volume: 1(5) Pages: 630-641
  • Peer Reviewed
• [Presentation] (2012)
  • Organizer: 日本呼吸器学学会総会
• [Presentation] (2012)
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: San Francisco
• [Presentation] Cellular senescence with insufficient autophagy of metaplastic epithelial cells in IPF. (2012)
  • Author(s): Jun Araya
  • Organizer: American Thoracic Society
  • Place of Presentation: San Francisco USA
  • Invited
• [Book] Annuall Reiew 呼吸器 (2013)
  • Author(s): 荒屋 潤、 原 弘道、桑野和善
  • Total Pages: 8
  • Publisher: 中外医学社