The exploration of new therapeutic target and the investigation of the role of maintaining alveolar-epithelium cell integrity in acute respiratory distress syndrome

• Project/Area Number: 26670419
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: University of Miyazaki
• Principal Investigator: Nakazato Masamitsu 宮崎大学, 医学部, 教授 (10180267)
• Co-Investigator(Kenkyū-buntansha): Tsubouchi Hironobu 宮崎大学, 医学部, 助教 (60573988) ; Matsumoto Nobuhiro 宮崎大学, 医学部, 助教 (70418838) ; Miura Ayako 宮崎大学, 医学部 (70710903)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 上皮統合性 / 肺損傷 / 急性呼吸窮迫症候群 / タイトジャンクション / リモデリング / グレリン / Ｐｔｅｎ / 基底膜 / Pten

Outline of Final Research Achievements

The pathological features of acute respiratory distress syndrome (ARDS) include injuries of alveolar epithelial cells (AECs) and destruction of the alveolar capillary barrier, which cause subsequent devastating lung fibrosis. Pten, a tumor suppressor gene, negatively regulates the PI3K/AKT pathway. To clarify the biological role of Pten in AEC in the pathogenesis of lung fibrosis, we used a AEC-specific null mutation of Pten mice (SOPten⊿/⊿). SOPten⊿/⊿ mice showed excessive lung fibrosis compared with the control after bleomycin administration. The expression of epithelial-mesenchymal transition (EMT) related molecules and the number of epithelial derived myofibroblasts were increased in the lungs of bleomycin-treated SOPten⊿/⊿ mice. Systemic administration of the Akt inhibitor ameliorated the BLM-induced lung injury. Our results indicate that Pten has the essential role in AEC integrity and they highlight the Pten/Akt pathway as a potential therapeutic target in ARDS.

Research Products

• [Journal Article] Ghrelin Administration for Chronic Respiratory Failure: A Randomized Dose-Comparison Trial. Lung (2015)
  • Author(s): Matsumoto N, Miki K, Tsubouchi H, Sakamoto A, Arimura Y, Yanagi S, Iiboshi H, Yoshida M, Souma R, Ishimoto H, Yamamoto Y, Yatera K, Yoshikawa M, Sagara H, Iwanaga T, Mukae H, Maekura R, Kimura H, Nakazato M, Kangawa K
  • Journal Title: Lung Volume: 193 Issue: 2 Pages: 239-247
  • DOI: 10.1007/s00408-015-9685-y
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice (2015)
  • Author(s): Kawaguchi M, Kanemaru A, Fukushima T, Yamamoto K, Tanaka H, Haruyama Y, Itoh H, Matsumoto N, Kangawa K, Nakazato M, Kataoka H
  • Journal Title: Cancer Sci. Volume: 106 Issue: 9 Pages: 1130-1136
  • DOI: 10.1111/cas.12725
  • Peer Reviewed / Open Access
• [Journal Article] Breakdown of epithelial barrier integrity and overdrive activation of alveolar epithelial cells in the pathogenesis of acute respiratory distress syndrome and lung fibrosis. (2015)
  • Author(s): Yanagi S, Tsubouchi H, Miura A, Matsumoto N, Nakazato M
  • Journal Title: Biomed Res Int Volume: 573210 Pages: 1-12
  • DOI: 10.1155/2015/573210
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ARDSと肺線維症の病態機構における肺胞上皮細胞統合性の役割 (2015)
  • Author(s): 柳 重久、坪内拡伸、松元信弘、中里雅光
  • Journal Title: 呼吸 Volume: 34 Pages: 554-559
• [Journal Article] Rikkunshito ameliorates bleomycin-induced acute lung injury in a ghrelin-independent manner. (2014)
  • Author(s): Tsubouchi H, Yanagi S, Miura A, Iizuka S, Mogami S, Yamada C, Hattori T, Nakazato M
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 306 Issue: 3 Pages: 233-245
  • DOI: 10.1152/ajplung.00096.2013
  • Peer Reviewed
• [Journal Article] Ghrelin relieves cancer cachexia associated with the development of lung adenocarcinoma in mice (2014)
  • Author(s): Tsubouchi H, Yanagi S, Miura A, Matsumoto N, Kangawa K, Nakazato M
  • Journal Title: Eur J Pharmacol Volume: 743 Pages: 1-10
  • DOI: 10.1016/j.ejphar.2014.09.025
  • Peer Reviewed
• [Journal Article] Rikkunshito ameliorates cachexia associated with bleomycin-induced lung fibrosis in mice by stimulating ghrelin secretion. (2014)
  • Author(s): Tsubouchi H, , Yanagi S, Miura A, Mogami S, Yamada C, Iizuka S, Hattori T, Nakazato M
  • Journal Title: Nutr Res Volume: 34 Issue: 10 Pages: 876-885
  • DOI: 10.1016/j.nutres.2014.08.014
  • Peer Reviewed
• [Journal Article] Autopsy analyses in acute exacerbation of idiopathic pulmonary fibrosis. (2014)
  • Author(s): Oda K, Ishimoto H, Yamada S, Kushima H, Ishii H, Imanaga T, Harada T, Ishimatsu Y, Matsumoto N, Naito K, Yatera K, Nakazato M, Kadota J, Watanabe K, Kohno S, Mukae H.
  • Journal Title: Respiratory Research Volume: １５ Issue: 1 Pages: 109-109
  • DOI: 10.1186/s12931-014-0109-y
  • NAID: 120006986405
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] ブレオマイシン誘発肺線維症モデルにおけるグレリンを介した六君子湯の摂食調節作用 (2014)
  • Author(s): 飯塚正一，柳 重久，坪内拡伸，十枝内厚次，最上祥子，山田ちひろ，服部智久，中里雅光
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: 宮崎
  • Year and Date: 2014-10-24 – 2014-10-25
• [Presentation] ブレオマイシン肺傷害モデルにおける六君子湯のグレリン分泌を介したcachexia改善効果 (2014)
  • Author(s): 坪内拡伸，柳 重久，松元信弘，中里雅光
  • Organizer: 第54回 日本呼吸器学会学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Book] Annual Review 2015呼吸器，（分担）呼吸器疾患におけるPTENの役割 (2015)
  • Author(s): 柳 重久、坪内拡伸、中里雅光
  • Total Pages: 248
  • Publisher: 中外医学社