Pathogenetic Mechanism for Hypersecretion of Mucin Glycoprotein in Cholelithiasis

• Project/Area Number: 09670509
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: University of Tsukuba
• Principal Investigator: SHODA Junichi Inst. Clin. Med., Tsukuba Univ. Assistant professor, 臨床医学系, 講師 (90241827)
• Project Period (FY): 1997 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 1999: ¥600,000 (Direct Cost: ¥600,000); Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 1997: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: cholelithiasis / mucin / arachidonate metabolism / phospholipase AィイD22ィエD2 / mucin gene / 肝内結石症 / ムチンコア蛋白遺伝子 / 胆管炎 / 結石成因 / ホスホリパーゼA_2受容体 / CFTR / 難治性疾患 / 硫酸ムチン

Research Abstract

Multiple cholesterol stones are associated with more biliary complications and exhibit more rapid cholesterol nucleation than solitary stones. Secretory or group II phospholipase AィイD22ィエD2 (PLAィイD22ィエD2-II) levels in gallbladder bile were significantly higher in patients with multiple cholesterol stones than in those with solitary stones or control subjects. Increased biliary PLAィイD22ィエD2-II levels in multiple cholesterol stones were associated with a concomitant increase in the protein and hexosamine concentrations as well as gallbladder bile viscosity. Increased PLAィイD22ィエD2-II in gallbladder bile may be of pathogenetic importance in patients with multiple cholesterol stones, probably through potentiating gallbladder mucosal inflammation with associated biliary alterations favoring cholesterol crystal formation.
Ursodeoxycholate (UDC) decreases biliary levels of various pronucleating proteins, possibly due to its membrane-protective effects on the inflamed gallbladder mucosa. Long-te rm UDC administration was observed to lower the increased PLAィイD22ィエD2-II protein mass and mRNA level as well as the PLAィイD22ィエD2-V mRNA level in the gallbladders of patients with multiple cholesterol stones, which in turn may be of therapeutic importance in improving the gallbladder mucosal inflammation. Effects of UDC on secretory low molecular weight PLAィイD22ィエD2s as inflammatory mediators may relate to the reported efficacy of UDC treatment in cholesterol gallstone disease.
Intrahepatic calculi is characterized by an intractable course and frequent recurrences. Chronic proliferative cholangitis may underlie the complex nature of the disease. PLAィイD22ィエD2-II levels were significantly higher in the bile from the stone-containing hepatic ducts than in the ductal bile from gallbladder stone patients. The increased sPLAィイD22ィエD2 levels were associated with a concomitant increase in prostaglandin EィイD22ィエD2 and total mucin concentrations. The affected bile ducts showed an increased mRNA level of PLAィイD22ィエD2-II compared with the ducts from control subjects. In intrahepatic calculi, an enhanced expression of the PLAィイD22ィエD2-II may be of pathophysiological significance for the chronic proliferative cholangitis, probably through biliary alterations favoring growth of preexisting stones and even further progressions.

Research Products

• [Publications] Shoda J.et al.: "Increased biliary group II phospholipase A_2 and altered〜"Gastroenterology. 112. 2036-2047 (1997)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kano M.et al.: "Effects of long-term ursodeoxycholate administration〜"Hepatology. 28. 302-312 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Shoda J.et al.: "Secretory low molecular weight phospholipase A_2〜"Hepatology. 29. 1026-1036 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ikegami T.et al.: "The chemopreventive role of ursodeoxycholic acid〜"Cancer Letter. 134. 129-139 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tomida S.et al.: "Long-term ursodeoxycholic acid therapy is〜"Hepatology. 30. 6-13 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Shoda, J., Ueda, T., Ikegami, T., Matsuzaki, Y., Satoh, S., Kano, M., Matsuura, K., Tanaka, N.: "Increased biliary group II phospholipase AィイD22ィエD2 and altered gallbladder bile in patients with multiple cholesterol stones."Gastroenterology. 112. 2036-2047 (1997)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kano, M., Shoda, J., Irimura, T., Ueda, T., Iwasaki, R., Urasaki, T., Kawauchi, Y., Asano, T., Matsuzaki, Y., Tanaka, N.: "Effects of long-term ursodeoxycholate administration on expression levels of secretory low molecular weight phospholipase AィイD22ィエD2 and mucin genes in gallbladders and biliary composition in patients with multiple cholesterol stones."Hepatology. 28. 302-313 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Shoda, J., Kano, M., Asano, T., Irimura, T., Ueda, T., Iwasaki, R., Furukawa, M., Kamiya, J., Nimura, Y., Todoroki, T., Matsuzaki, Y., Tanaka, N.: "Secretory low molecular weight phospholipase AィイD22ィエD2 and their specific receptor in bile ducts of patients with intrahepatic calculi-factors of pathophysiological significance for chronic proliferative cholangitis."Hepatology. 29. 1026-1036 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 田中 直見,正田 純一他: "肝内結石症の発生,進展にかかわる分泌型低分子ホスホリパーゼA_2とムチン遺伝子の発現"厚生省特定疾患肝内結石症調査研究班平成9年度報告書. 23-27 (1998)
• [Publications] 正田 純一他: "肝内結石症におけるホスホリパーゼA_2とムチン遺伝子の発現"胆と膵. 19. 1037-1041 (1998)
• [Publications] Kano M and Shoda J. et al.: "Effects of long-term ursodeoxycholate administration on expression levels of secretory low-molecular-weight phospholipase A_2 and mucin genes in"Hepatology. 28. 302-313 (1998)
• [Publications] Shoda J,et al.: "Secretory low-molecular-weight phospholipase A_2 and their specific receptor in bile ducts of patients with intrahepatic calculi: factors of"Hepatology. 29. 1026-1036 (1999)
• [Publications] Kano M and Shoda J,et al.: "Effects of long-term ursodeoxycholate administration on expression levels of secretory low-molecular-weight phospholipase A2 and mucin genes in gallbladders and biliary composition" Hepatology. 28. 302-313 (1998)
• [Publications] Shoda J,et al.: "Secretory low-molecular-weight phospholipase A2 and their specific receptor in bile ducts of patients with intrahepatic calculi: factors of chronic proliferative cholalngitis" Hepatology. 29(in press). (1999)
• [Publications] Shoda J: "Simultaneous determination of plasma mevalonate and 7α-hydroxy-4-cholesten-3-one levels in hyperlipoproteinemia" Hepatology. 25. 18-26 (1997)
• [Publications] Shoda J: "Increased biliary group II phospholipase A_2 and altered gallbladder bile in patients with multiple cholesterol stones." Gastroenterology. 112. 2036-2047 (1997)