Analyses of the effects of hypoxia on the progression of liver disease and hepatic carcinogenesis.

• Project/Area Number: 25461000
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyushu University
• Principal Investigator: Kato Masaki 九州大学, 大学病院, 助教 (60444808)
• Co-Investigator(Kenkyū-buntansha): Kotoh Kazuhiro 九州大学, 大学病院, 講師 (80289579)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 低酸素 / 肝線維化 / 肝発癌 / 肝星細胞 / 末梢血単核球 / indian hedgehog / adrenomedullin / p21 / hedgehog / HO-1 / VEGFA / VEGFR2 / 慢性肝炎 / 肝硬変 / 類洞血流 / 定量的PCR

Outline of Final Research Achievements

Intrahepatic hypoxia may enhance liver fibrosis and stimulate hepatic carcinogenesis in chronic liver disease. In thioacetamide induced rat chronic liver injury model, we observed the presence of hypoxia in liver parenchyma in the early period of injury and the activation of hepatic stellate cell, probably due to the down-regulation of Indian hedgehog. Then we analyzed the mRNA expression levels of hypoxia responsible genes in the peripheral blood mononuclear cells isolated from the patients with chronic liver disease. We observed the enhanced expressions of hypoxia response genes (HIF1, HO-1), and angiogenesis regulating genes (VEGFA, Adrenomedullin), which may suggest the presence of intrahepatic hypoxia. Corresponding expression of p21, a gene sensitive to DNA injury, was also elevated, suggesting the intrahepatic hypoxia may be involved in the DNA injury, leading to the increase of the risk of liver cancer.

Research Products

• [Journal Article] Intrahepatic microcirculatory disorder, parenchymal hypoxia and NOX4 upregulation result in zonal differences in hepatocyte apoptosis following lipopolysaccharide- and D-galactosamine-induced acute liver failure in rats. (2014)
  • Author(s): Tanaka M, Tanaka K, Masaki Y, Miyazaki M, Kato M, Kotoh K, Enjoji M, Nakamuta M, Takayanagi R.
  • Journal Title: Int J Mol Med. Volume: 33 Issue: 2 Pages: 254-62
  • DOI: 10.3892/ijmm.2013.1573
  • Peer Reviewed
• [Presentation] 末梢血単核球を用いた慢性疾患患者における低酸素ストレスと炎症マーカー、血管新生関連因子の評価 (2016)
  • Author(s): 桑野哲史、田中紘介、山崎晃裕、大橋朋子、加藤正樹、古藤和浩
  • Organizer: 第52回日本肝臓学会
  • Place of Presentation: 千葉
  • Year and Date: 2016-05-19
• [Presentation] 末梢血単核球を用いた、慢性肝疾患症例の低酸素ストレスレベルの評価の可能性 (2014)
  • Author(s): 田中紘介, 田中正剛, 真崎由子, 山崎晃裕, 原田林, 梅野成大, 加藤 正樹, 遠城寺宗近, 中牟田誠, 古藤 和浩, 髙栁 涼一
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] チオアセトアミド投与ラット肝硬変モデルにおける肝星細胞活性化とヘッジホッグシグナルの関連性についての組織学的検討 (2014)
  • Author(s): 田中正剛、加藤正樹、田中紘介、宮崎将之、古藤和浩
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-29 – 2014-05-30