Approaches to the pathogenesis and treatment of liver fibrosis through genetically modified mice.

• Project/Area Number: 24590967
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Mie University
• Principal Investigator: IWASA Motoo 三重大学, 医学(系)研究科(研究院), 准教授 (80378299)
• Co-Investigator(Kenkyū-buntansha): GABAZZA Esteban 三重大学, 医学系研究科, 教授 (00293770)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: アルコール性肝障害 / プロテインS / NKT細胞 / TAFI / 肝線維化 / 凝固線溶系

Outline of Final Research Achievements

This study investigated the role of protein S in acute alcoholic hepatitis. A mouse overexpressing human protein S (hPS-TG) was generated in which acute hepatitis was induced by intraperitoneal injection of ethanol. The levels of serum liver enzymes, liver tissue inflammatory cytokines and the degree of hepatic steatosis were significantly increased in hPS-TG mice treated with ethanol. Cell expansion, activation and inhibition of apoptosis were significantly augmented in natural killer T (NKT) cells from hPS-TG mice. In a co-culture system of hepatocytes and NKT cells, the effects of protein S on ethanol-mediated cell injury were suppressed by a CD1d neutralizing antibody. NKT cells from patients with alcoholic hepatitis had increased levels of protein S and CD1d mRNA. Protein S exacerbates acute alcoholic hepatitis by enhancing the activation of NKT cells, indicating that protein S may be a molecular target for therapy of this disease.

Research Products

• [Journal Article] Protein S exacerbates alcoholic hepatitis by stimulating liver natural killer T cells. (2015)
  • Author(s): Chelakkot-Govindalayathil AL, Mifuji-Moroka R, D'Alessandro-Gabazza CN, Toda M, Matsuda Y, Gil-Bernabe P, Roeen Z, Yasuma T, Yano Y, Gabazza EC, Iwasa M, Takei Y.
  • Journal Title: J Thromb Haemost. Volume: １３（１） Issue: 1 Pages: 142-154
  • DOI: 10.1111/jth.12789
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] アルコール性肝障害におけるProtein Sの肝NKT細胞活性化を介した病態への関与 (2015)
  • Author(s): 諸岡 留美, 岩佐 元雄, 長谷川 浩司, ガバザ・エステバン , 竹井 謙之
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本
  • Year and Date: 2015-05-21 – 2015-05-22
• [Presentation] Protein SはNKT細胞の活性化を介して急性アルコール性肝障害を増悪させる (2014)
  • Author(s): 諸岡 留美, 岩佐 元雄, 杉本 龍亮, 宮地 洋英, 田中 秀明, 藤田 尚己, 小林 由直, ガバザ・エステバン , 竹井 謙之
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ東京
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] Protein SはNKT細胞の活性化を介して急性アルコール性肝障害を増悪させる (2014)
  • Author(s): 諸岡留美、岩佐元雄、ガバザエステバン、竹井謙之
  • Organizer: 第50回肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] Protein S exacerbates acute alcohol-induced liver injury by enhancing activation of liver natural killer T cells (2013)
  • Author(s): Hirohide Miyachi, Rumi Moroka, Naoki Fujita, Yoshinao Kobayashi, Motoh Iwasa, Esteban C Gabazza* and Yoshiyuki Takei
  • Organizer: 第64回米国肝臓学会
  • Place of Presentation: ワシントン
• [Presentation] 急性アルコール性肝障害における自然免疫、特にNKTの関与―Protein Sを用いた検討 (2013)
  • Author(s): 諸岡 留美, 杉本 龍亮, 宮地 洋英, 田中 秀明, 藤田 尚己, 小林 由直, 岩佐 元雄, ガバザ・エステバン , 竹井 謙之
  • Organizer: 肝臓学会総会
  • Place of Presentation: 東京