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Research of Immune Response viaToll-like Receptors and Infection Control in Severe Acute Pancreatitis

Research Project

Project/Area Number 18591515
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionKobe University

Principal Investigator

SHINZEKI Makoto (2007)  Kobe University, Hospital Surgery, Medical Staff (60444593)

上田 隆 (2006)  神戸大学, 医学部附属病院, 助手 (80346262)

Co-Investigator(Kenkyū-buntansha) KURODA Yoshikazu  Kobe University, Graduate school of Medical Science, Surgeiy, Professor (70178143)
安田 武生  神戸大学, 医学部附属病院, 医員 (20403248)
新関 亮  神戸大学, 医学部附属病院, 医員 (60444593)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,130,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Keywordssevere acute pancreatitis / toll-like receptors(TLR) / HMGB1 / inflammation / immune response / organ dysfunction / infection / Toll受容体
Research Abstract

1. Expression of toll-like receptors (TLR), immune response via TLR, and role of TLR in severe acute pancreatitis (SAP)
1) On alveolar macrophages from rats with SAP, expressions of TLR2 and TLR4 (mRNA and protein) were significantly decreased, and cytokine production was also significantly diminished.
2) In intestinal mucosa in rats with SAP, TLR2 and TLR4 were expressed at the top of villi and crypt (especially at Paneth cells). The expressions of TLR2 and TLR4 proteins and NFκB activation were increased in the early phase and decreased in the late phase.
3) The TLR4-deficient mice had significantly lower serum levels of AST, ALT, BUN, and creatinine; significantly lower serum levels of IL-1 and TNF; reduced apoptosis of the liver and kidney; and a significantly higher rate of positive gram-negative bacterial cultures of the pancreas.
2. Expression of HMGB1 and its significance in severe acute pancreatitis
1) Serum HMGB1 levels were significantly increased in patients with SAP and were correlated with disease severity.
2) Serum HMGB1 levels were significantly increased in experimental SAP and expression of HMGB1 was increased in major organs (pancreas, liver, kidney, lung, and small intestine) injured during SAP.
3) Blockade of HMGB1 by anti-HMGB1 antibody attenuated the development of SAP and associated organ dysfunction, but worsened the bacterial translocation to pancreas.
3. Blood levels of new mediators related to immune response in severe acute pancreatitis
1) Serum IL-15 levels were increased significantly in severe acute pancreatitis, and they were correlated with severity scores. Serum IL-15 levels were greater in patients with organ dysfunction, patients with infection, and nonsurvivors.
2) Serum LAP levels were elevated in patients with SAP but were significantly lower in patients with higher grade of severity or pancreatic necrosis.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (46 results)

All 2008 2007 2006 Other

All Journal Article (25 results) (of which Peer Reviewed: 11 results) Presentation (21 results)

  • [Journal Article] Expression of toll-like receptor 2 and 4 in intestinal mucosa in exper imental severe acute pancreatitis2008

    • Author(s)
      Hidehiro Sawa
    • Journal Title

      Hepatogastroenterology (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Increase of high mobility group box chromosomal protein 1 in blood and injured organs in experimental severe acute pancreatitis2007

    • Author(s)
      Takeo Yasuda
    • Journal Title

      Pancreas 34・4

      Pages: 487-488

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Serum interleukin-15 level is a useful predictor of the complications and mortality in severe acute pancreatitis2007

    • Author(s)
      Takashi Ueda
    • Journal Title

      Surgery 142・3

      Pages: 319-326

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Role of toll-like receptor 4 in the pathophysiology of severe acute pancreatitis in mice2007

    • Author(s)
      Hidehiro Sawa
    • Journal Title

      Surgery Today 37・10

      Pages: 867-873

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Serum immunosuppressive acidic protein levels in patients with severe acute pancreatitis2007

    • Author(s)
      Makoto Shinzeki
    • Journal Title

      Pancreas 35・4

      Pages: 327-333

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Decreased expression of toll-like receptor 2 and 4 on macrophages in experimental severe acute pancreatitis2007

    • Author(s)
      Naoki Matsumura
    • Journal Title

      Kobe Journal of Medical Sciences 53・5

      Pages: 219-227

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Expression of toll-like receptor 2 and 4 in intestinal mucosa in experimental severe acute pancreatitis2007

    • Author(s)
      Hidehiro Sawa
    • Journal Title

      Hepatogastroenterology (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Increase of high mobility group box chromosomal protein 1 in blood and injured organs in experimental severe acute pancreatitis2007

    • Author(s)
      Takeo, Yasuda
    • Journal Title

      Pancreas 34-4

      Pages: 487-488

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Serum interleukin-15 level is a useful predictor of the complications and mortality in severe acute pancreatitis2007

    • Author(s)
      Takashi, Ueda
    • Journal Title

      Surgery 142-3

      Pages: 319-326

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Role of toll-like receptor 4 in the pathophysiology of severe acute pancreatitis in mice2007

    • Author(s)
      Hidehiro, Sawa
    • Journal Title

      Surgery Today 37-10

      Pages: 319-326

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Serum immunosuppressive acidic protein levels in patients with severe acute pancreatitis2007

    • Author(s)
      Makoto, Shinzeki
    • Journal Title

      Pancreas 35-4

      Pages: 327-333

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Decreased expression of toll-like receptor 2 and 4 on macrophhes in experimental severe acute pancreatitis2007

    • Author(s)
      Naoki, Matsumura
    • Journal Title

      Kobe Journal of Medical Sciences 53-5

      Pages: 219-227

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Role of toll-like receptor 4 in the pathophysiology of mice severe acute pancreatitis2007

    • Author(s)
      Hidehiro Sawa
    • Journal Title

      Surgery Today 37・10

      Pages: 867-873

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Decreased expression of toll-like receptor 2 and 4 on macrophages in experimental severe acute pancreatitis2007

    • Author(s)
      Naoki Matsumura
    • Journal Title

      Kobe Journal of Medical Sciences 53-5

      Pages: 219-227

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Significant increase of serum high mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis2006

    • Author(s)
      Takeo Yasuda
    • Journal Title

      Pancreas 33・4

      Pages: 359-363

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Blockade of high mobility group box-1 protein (HMGB1) attenuates experimental severe acute pancreatitis2006

    • Author(s)
      Hidehiro Sawa
    • Journal Title

      World Journal of Gastroenterology 12・47

      Pages: 7666-7670

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Significant increase of serum high mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis2006

    • Author(s)
      Takeo, Yasuda
    • Journal Title

      Pancreas 33-4

      Pages: 359-363

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Blockade of high mobility group box-1 protein (HMGB 1) attenuates experimental severe acute pancreatitis2006

    • Author(s)
      Hidehiro, Sawa
    • Journal Title

      World Journal of Gastroenterology 12-47

      Pages: 7666-7670

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Blockade of high mobility group box-1 protein (HMGB 1) attenuates experimental severe acute pancreatitis2006

    • Author(s)
      Hidehiro Sawa
    • Journal Title

      World Journal of Gastroenterology 12・47

      Pages: 7666-7670

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Significant elevation of serum high mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis2006

    • Author(s)
      Takeo Yasuda
    • Journal Title

      Pancreas 33・4

      Pages: 359-363

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expression of toll-like receptor 2 and 4 in intestinal mucosa in experimental severe acute pancreatitis

    • Author(s)
      Hidehiro, Sawa
    • Journal Title

      Hepatogastroenterology (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Increase of high mobility group box chromosomal protein 1 in blood and injured organs in experimental severe acute pancreatitis

    • Author(s)
      Takeo Yasuda
    • Journal Title

      Pancreas (In press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Role of toll-like receptor 4 in the pathophysiology of mice severe acute pancreatitis

    • Author(s)
      Hidehiro Sawa
    • Journal Title

      Surgery Today (In press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expression of toll-like receptor 2 and 4 in intestinal mucosa in experimental severe acute pancreatitis

    • Author(s)
      Hidehiro Sawa
    • Journal Title

      Hepatogastroenterology (In press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Decreased expression of toll-like receptor 2 and 4 on macrophages in experimental severe acute pancreatitis

    • Author(s)
      Naoki Matsumura
    • Journal Title

      Kobe Journal of Medical Sciences (In press)

    • Related Report
      2006 Annual Research Report
  • [Presentation] 重症急性膵炎における血清IL-15値の上昇と臨床的有用性2007

    • Author(s)
      上田 隆
    • Organizer
      第49回日本消化器病学会大会
    • Place of Presentation
      神戸
    • Year and Date
      2007-10-20
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Rat急性膵炎モデルにおけるHigh Mobility Group Box Chromosomal Protein 1 (HMGB1)の動態2007

    • Author(s)
      安田武生
    • Organizer
      第62回日本消化器外科学会
    • Place of Presentation
      東京
    • Year and Date
      2007-07-19
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Rat急性膵炎モデルにおけるHigh Mobility Group Box Chromosomal Protein 1(HMGB1)の動態2007

    • Author(s)
      安田武生
    • Organizer
      第62回日本消化器外科学会
    • Place of Presentation
      東京
    • Year and Date
      2007-07-19
    • Related Report
      2007 Annual Research Report
  • [Presentation] マウス重症急性膵炎モデルに対する抗HMGB1中和抗体の効果2007

    • Author(s)
      沢 秀博
    • Organizer
      第38回日本膵臓学会大会
    • Place of Presentation
      福岡
    • Year and Date
      2007-06-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Effects of toll-like receptor 4-deficiency in the pathophysiology of experimental severe acute pancreatitis2007

    • Author(s)
      Hidehiro Sawa
    • Organizer
      The Annual Meeting of American Gastroenterological Association
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Role of high mobility group box chromosomal protein 1 in experimental severe acute pancreatitis2007

    • Author(s)
      Takeo Yasuda
    • Organizer
      The Annual Meeting of American Gastroenterological Association
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Significant elevation of serum IL-15 levels in patients with severe acute pancreatitis2007

    • Author(s)
      Kozo Takase
    • Organizer
      The 48th Annual Meeting of the Society for Surgery of the Alimentary Tract
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Effects of toll-like receptor 4-deficiency in the pathophysiology of experimental severe acute pancreatitis2007

    • Author(s)
      Hidehiro, Sawa
    • Organizer
      American Gastroenterological Association
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Role of high mobility group box chromosomal protein I in experimental severe acute pancreatitis2007

    • Author(s)
      Takeo, Yasuda
    • Organizer
      American Gastroenterological Association
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Significant elevation of serum IL-15 levels in patients with severe acute pancreatitis2007

    • Author(s)
      Kozo, Takase
    • Organizer
      Society for Surgery of the Alimentary Tract
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Effects of toll-like receptor 4-deficiency in the pathophysiology of experimental severe acute pancreatitis2007

    • Author(s)
      Hidehiro Sawa
    • Organizer
      The American Gastroenterological Association Annual Meeting
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Related Report
      2007 Annual Research Report
  • [Presentation] Role of high mobility group box chromosomal protein 1 in experimental severe acute pancreatitis2007

    • Author(s)
      Takeo Yasuda
    • Organizer
      The American Gastroenterological Association Annual Meeting
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Related Report
      2007 Annual Research Report
  • [Presentation] Significant elevation of serum IL-15 levels in patients with severe acute pancreatitis2007

    • Author(s)
      Kozo Takase
    • Organizer
      48th Annual Meeting of the Society for Surgery of the Alimentary Tract
    • Place of Presentation
      Washington DC
    • Year and Date
      2007-05-21
    • Related Report
      2007 Annual Research Report
  • [Presentation] マウス重症急性膵炎におけるToll-like receptor4欠損の影響2007

    • Author(s)
      沢 秀博
    • Organizer
      第93回日本消化器病学会総会
    • Place of Presentation
      青森
    • Year and Date
      2007-04-19
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] 重症急性膵炎の臓器障害とbacterial translocationにおけるToll-like receptorの関与2007

    • Author(s)
      沢 秀博
    • Organizer
      第107回日本外科学会総会
    • Place of Presentation
      大阪
    • Year and Date
      2007-04-12
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Prevention of infectious complications in severe acute pancreatitis2007

    • Author(s)
      Takeo Yasuda
    • Organizer
      The Congress of Asian-Pacific Hepato-Pancreato-Biliary Association
    • Place of Presentation
      Fukuoka
    • Year and Date
      2007-03-23
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] TLR expression and NF-κB activation in intestinal mucosa in experimental severe acute pancreatitis2007

    • Author(s)
      Hidehiro Sawa
    • Organizer
      The Congress of Asian-Pacific Hepato-Pancreato-Biliary Association
    • Place of Presentation
      Fukuoka
    • Year and Date
      2007-03-23
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Prevention of infectious complications in severe acute pancreatitis2007

    • Author(s)
      Takeo, Yasuda
    • Organizer
      Asian-Pacific Hepato-Pancreato-Biliary Association
    • Place of Presentation
      Fukuoka
    • Year and Date
      2007-03-13
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] TLR expression and NF-613 activation in intestinal mucosa in experimental severe acute pancreatitis2007

    • Author(s)
      Hidehiro, Sawa
    • Organizer
      Asian-Pacific Hepato-Pancreato-Biliary Association
    • Place of Presentation
      Fukuoka
    • Year and Date
      2007-03-13
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 重症急性膵炎における血清IAP値の上昇2006

    • Author(s)
      新関 亮
    • Organizer
      第48回日本消化器病学会大会
    • Place of Presentation
      札幌
    • Year and Date
      2006-10-12
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 重症急性膵炎症例における血清High Mobility Group Box Chromosomal Protein1(HMGB1)値の上昇2006

    • Author(s)
      安田武生
    • Organizer
      第48回日本消化器病学会大会
    • Place of Presentation
      札幌
    • Year and Date
      2006-10-12
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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