Development of a novel therapy for rheumatoid arthritis utilizing ATPase inhibitor

• Project/Area Number: 22659276
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: SAKAI Ryo 京都府立医科大学, 医学研究科, 研修員 (50543542)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: ATPase阻害 / proton pump inhibitor / 抗炎症作用 / 関節リウマチ / 関節疾患 / 破骨細胞

Research Abstract

Aberrantly activated macrophages, which overproduce inflammatory mediators, are involved in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. We analyzed the anti-inflammatory activity of lansoprazole(LPZ), a typical proton pump(P-ATPase) inhibitor, on RAW264.7 murine macrophages. Treatment of lipopolysaccharide(LPS)-stimulated RAW264.7 cells with LPZ inhibited the production of nitric oxide(NO) and prostaglandin E2(PGE2). Since P-ATPase expression was not observed in RAW264.7 cells, the anti-inflammatory effect of LPZ was independent of ATPase. In contrast, diphenylene iodonium(DPI), an inhibitor of nicotinamide adenine dinucleotide phosphate(NADPH) oxidase, decreased NO but not PGE2 levels. LPZ suppressed the LPS-stimulated production by RAW264.7 cells of reactive oxygen species(ROS), which plays an important role in inflammatory responses. ROS elevation in these cells was associated with NO but not PGE2 production, suggesting that LPZ inhibits NO production by suppressing NADPH oxidase activity. These findings suggest that LPZ may be useful in the treatment of many inflammatory diseases associated with activated macrophages.

Research Products

• [Journal Article] Lansoprazole Inhibits Nitric Oxide and Prostaglandin E2 Production in Murine Macrophage RAW 264.7 Cells (2012)
  • Author(s): Shuji Nakagawa, Yuji Arai, Tsunao Kishida, Nobuyuki Hiraoka, Shinji Tsuchida, Hiroaki Inoue, Ryo Sakai, Osam Mazda, Toshikazu Kubo
  • Journal Title: Inflammation Volume: Vol.35 Issue: 3 Pages: 1062-1068
  • DOI: 10.1007/s10753-011-9412-7
  • Peer Reviewed
• [Presentation] ランソプラゾールのマクロファージに対する抗炎症効果の解析関節リウマチへの応用を目指して (2011)
  • Author(s): 井上裕章, 新井祐志, 中川周士, 寺内竜, 平岡延之, 土田真嗣, 酒井亮, 松田修, 久保俊一
  • Organizer: 第26回日本整形外科学会基礎学術集会
  • Place of Presentation: ベイシア文化ホール(群馬県)
  • Year and Date: 2011-10-20
• [Presentation] Analysis of anti-inflammatory effects of lansoprazole on macrophages (2011)
  • Author(s): Hiroaki Inoue, Yuji Arai, Shuji Nakagawa, Ryu Terauchi, Nobuyuki Hiraoka, Shinji Tsuchida, Ryo Sakai, Osam Mazda, Toshikazu Kubo
  • Organizer: 14th World Congress of the Osteoarthritis Research Society International(OARSI)
  • Place of Presentation: Hilton San Diego Bayfront(San Diego, CA, USA)
• [Presentation] Analysis of anti-inflammatory effects of lansoprazole on macrophages (2011)
  • Author(s): Inoue H, Arai Y, Nakagawa S, Terauchi R, Hiraoka N, Tsuchida S, Sakai R, Mazda O, Kubo T
  • Organizer: 14th World Congress of the Osteoarthritis Research Society International (OARSI)
  • Place of Presentation: Hilton San Diego Bayfront (San Diego, CA)
• [Presentation] The role of gap junction for inflammatory cytokines in fibroblast-like synoviocytes of joint disease (2010)
  • Author(s): Shinji Tsuchida
  • Organizer: 13^<th> World Congress of Osteoarthritis
  • Place of Presentation: Brussels, Belgium