膵星細胞の活性化機構の解明と膵星細胞をターゲットにした新しい膵炎治療法の開発

• Project/Area Number: 14770227
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Tohoku University
• Principal Investigator: 正宗 淳 東北大学, 医学部附属病院, 助手 (90312579)
• Project Period (FY): 2002 – 2003
• Project Status: Completed (Fiscal Year 2003)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: 膵星細胞 / 慢性膵炎 / MAP kinase / Rho / 酸化ストレス / 急性膵炎 / 膵線維化 / アルコール / MAP kinases / シグナル伝達 / PPAR

Research Abstract

シグナル伝達をターゲットとした膵星細胞の活性化制御についてin vitroの系で検討した。Wister系雄性ラットより膵星細胞を分離し実験に用いた。p38mitogen-activated protein kinase (p38 MAPK)阻害剤であるSB203580、c-jun N-terminal kinase (JNK)阻害剤であるSP600125、Rho-Rho kinase系阻害剤であるY-27632、または抗酸化剤であるN-acetyl-cysteine (NAC)にて処理し、膵星細胞活性化の指標として、(1)α-smooth muscle actin (αSMA)発現、(2)細胞形態、(3)細胞増殖、(4)I型collagen産生、(5)monocyte chemoattractant protein-1 (MCP-1)産生を、各々検討した。SB203580処理により、(1)静止期膵星細胞の培養による活性化の抑制、(2)platelet-derived growth factor (PDGF)刺激による増殖の抑制、(3)α1(I)procollagen遺伝子発現の低下、(4)interleukin-1β (IL-1β)によるMCP-1産生誘導の抑制が認められた。SP600125およびNACでもほぼ同様の結果が得られた。一方、Y-27632は、静止期星細胞の活性化、細胞増殖、I型collagen産生には同様の抑制作用を認めたが、IL-1βによるMCP-1産生誘導を抑制しなかった。以上より、各種シグナル阻害剤や抗酸化剤が膵星細胞の活性化を抑制し、膵の炎症や線維化の治療につながる可能性が示唆された。

Research Products

• [Publications] A.Masamune et al.: "Establishment and Characterization of a Rat Pancreatic Stellate Cell Line by Spontaneous immortalization"World Journal of Gastroenterology. 9. 2751-2758 (2003)
• [Publications] A.Masamune et al.: "Specific Rho kinase inhibitors block activation of pancreatic stellate cells"Br J Pharmacol. 140. 1292-1302 (2003)
• [Publications] A.Masamune et al.: "Differential roles of signaling pathways for proliferation and migration of rat pancreatic stellate cells"Tohoku J Exp Med. 199. 69-84 (2003)
• [Publications] Y.Sakai et al.: "Macrophage migration inhibitory factor is a critical mediator of severe acute pancreatitis"Gastroenterology. 124. 725-736 (2003)
• [Publications] A.Masamune et al.: "Inhibition of p38 mitogen-activated protein kinase blocks activation of rat pancreatic stellate cells"J Pharmacol Exp Ther. 304. 8-14 (2003)
• [Publications] K.Kikuta et al.: "4-hydroxy-2,3-nonenal activates activator protein-1 and mitogen-activated protein kinases in rat pancreatic stellate cells"World Journal of Gastroenterology. (In press). (2004)
• [Publications] Masamune A, et al.: "Ligands of peroxisome proliferator-activated receptor-γ block activation of pancreatic stellate cells"J Biol Chem. 277. 141-147 (2002)
• [Publications] Masamune A, et al.: "Alchol activates activator protein-1 and MAP kinases in rat pancreatic stellate cells"J Pharmacol Exp Ther. 302. 36-42 (2002)
• [Publications] Masamune A, et al.: "Activated rat pancreatic stellate cells express intercellular adhesion molecule-1 (ICAM-1) in vitro"Pancreas. 25. 78-85 (2002)
• [Publications] Satoh M, Masamune A, et al.: "IEstablishment and characterization of a simian virus 40-immortalized rat pancreatic stellate cell line"Tohoku J Exp Med. 198. 55-69 (2002)
• [Publications] Masamune A, et al.: "Inhibition of p38 mitogen-activated protein kinase blocks activation of rat pancreatic stellate cells"J Pharmacol Exp Ther. 304. 8-14 (2003)
• [Publications] Masamune et al.: "Differential roles of signaling pathways for proliferation and migration of rat Pancreatic stellate cells"Tohoku J Exp med. (In press). (2003)