Investigation of the possibility of Trefoil Factor Family as a therapeutics for post-EMR (endoscopic mucosal resection) gastric ulcer

• Project/Area Number: 16390386
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: The Tazuke Kofukai
• Principal Investigator: KANAI Michiyuki The Tazuke Kofukai, Medical Research Institute 2nd Division, Chief Researcher, 医学研究所第2研究部, 研究主幹 (00322652)
• Co-Investigator(Kenkyū-buntansha): OHASHI Sinya The Tazuke Kofukai, Medical Research Institute 3rd Division, Researcher, 医学研究所第3研究部, 研究員 (20435556) ; HASHIDA Hiroki The Tazuke Kofukai, Medical Research Institute 2nd Division, Researcher, 医学研究所第2研究部, 研究員 (70281607) ; 鷹巣 晃昌 (財)田附興風会, 医学研究所・第1研究部, 研究主幹 (90399345) ; 木下 浩一 財団法人田附興風会, 医学研究所・第2研究部, 研究員 (60342698)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥13,700,000 (Direct Cost: ¥13,700,000); Fiscal Year 2006: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2005: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2004: ¥7,300,000 (Direct Cost: ¥7,300,000)
• Keywords: Epithelial wound healing / promoter of epithelial repair / Trefoil factor family / Intestinal trefoil factor / Endoscopic mucosal resection / artificial gastric ulcer / 消化管の創傷治癒 / 人工潰瘍

Research Abstract

Intesitnal trefoil factor (ITF) plays an important role in the process of wound healing of gastrointestinal tract. Endoscopic mucosal resection (EMR) is a prevailing procedure for the treatment of early gastric cancers. Following the procedure, patients need limited diet or medication such as anti-acid or muco-protective drugs for the protection of denuded area or facilitating the healing of the artificial ulceration. We have investigated if ITF could be useful as the therapeutics for the artificial ulceration caused by endoscopic mucosal resection (EMR). The effect of ITF was tested in a rat stomach model of EMR. The level of ITF gene expression in rat stomach was almost undetectable. Increased endogenous expression of ITF was observed on 1 day after EMR and maximum level was observed on day 3, which was examined by RT-PCR. Although exogenous ITF sprayed upon ulcer surface stayed only up to postoperative day 1, ITF significantly accelerated the mucosal healing in macroscopically as we ll as microscopically. The characteristic appearances of ulcer healing treated by ITF were attenuated the extent or the degree of inflammation, reduced necrosis of epithelial cells adjacent to the ulcer, enhanced re-epithelization of ulcer surface and decreased fibrosis. In aggregate, ITF accelerated the healing of artificial ulceration in a manner similar to natural healing process of gastric ulcer. In the view point of safety of ITF as clinical therapeutics, the stimulatory effect of TFF3 on proliferative response was evaluated in either endogenous TFF3 positive or negative gastric cancer cell lines. ITF did not have any stimulatory effect on all cell lines tested, which suggesting that ITF might be a effective therapeutics for the ulcerations caused by EMR for the management of carcinomas. In summary, our present study demonstrated the clinical importance of restitution, which is an initial phase of epithelial wound healing and promoted by exogenous administration of ITF. ITF might be a new therapeutics against post-EMR gastric ulceration.

Research Products

• [Journal Article] Preventive Effect of a Traditional Herbal Medicine, Hochu-ekki-to, on Immunosuppression Induced by Surgical Stress. (2007)
  • Author(s): Kimura M, Sasada S, Kanai M, Kawai Y, Yoshida Y, Hayashi E, Iwata S, Takabayashi A
  • Journal Title: Surgery Today. (in press)
  • NAID: 10021284484
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Intra-arterial continuous infusion chemotherapy with 5-fluorouracil and cisplatin improves the prognosis of locally advanced pancreatic cancer patients. (2007)
  • Author(s): Sasada T, Denno R, Tanaka T, Kanai M, Mizukami Y, Kohno S, Takabayashi A
  • Journal Title: Annual of Surgical Oncology. (inpress)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. (2007)
  • Author(s): Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H, Hosogi H, Aoki M, Oshima M, Hattori M, Takabayashi A, Minato N, Taketo MM
  • Journal Title: Nature Genetics. 39(4) Pages: 467-475
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 化学療法による全身リンパ節転移の消失後、原発巣切除により長期無再発生存している直腸未分化癌の1例 (2007)
  • Author(s): 木下浩一, 金井陸行, 高林有道
  • Journal Title: 日本消化器外科学会雑誌. 40(4) Pages: 504-509
  • NAID: 110006242604
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 膵管出血をきたした退形成性膵管癌の1例 (2007)
  • Author(s): 水上陽, 笹田哲朗, 橋田裕毅, 水本明良, 佐藤正人, 上田修吾, 田中基文, 郡司周太郎, 大石賢玄, 小山幸法, 吉田昌弘, 金井陸行, 鷹巣晃昌, 高林有道
  • Journal Title: 膵臓 22(4)(in press)
  • NAID: 10024366572
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Preventive Effect of a Traditional Herbal Medicine, Hochu-ekki-to, on Immunosuppression Induced by Surgical Stress. (2007)
  • Author(s): Kimura M, Sasada S, Kanai M, Kawai Y, Yoshida Y, Hayashi E, Iwata S, Takabayashi A.
  • Journal Title: Surgery Today (in press)
  • NAID: 10021284484
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intra-arterial continuous infusion chemotherapy with 5-fluorouracil and cisplatin improves the prognosis of locally advanced pancreatic cancer patients. (2007)
  • Author(s): Sasada T, Denno R, Tanaka T, Kanai M, Mizukami Y, Kohno S, Takabayashi A.
  • Journal Title: Annual of Surgical Oncology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. (2007)
  • Author(s): Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H, Hosogi H, Aoki M, Oshima M, Hattori M, Takabayashi A, Minato N, Taketo MM.
  • Journal Title: Nature Genetics 39(4) Pages: 467-475
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A case report of non-recurred long-term survival after resection for undifferentiated rectal cancer with systemic multiple lymph node metastases successfully treated by preoperative chemotherapy. (2007)
  • Author(s): Kinoshita K, Kanai M, Takabayashi A.
  • Journal Title: Jpn.Gastroenterol Surg. 40(4) Pages: 504-509
  • NAID: 110006242604
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 「研究成果報告書概要(欧文)」より (2007)
  • Author(s): Mizukami Y, Sasada T, Hashida H, Mizumoto A, Satoh M, Ueda S, Tanaka M, Gunji S, Oishi M, Koyama Y, Yoshida M, Kanai M, Takasu K, Takabayashi A.
  • Journal Title: Jpn.Pancreas. 22(4)(in press)
• [Journal Article] Preventive Effect of a Traditional Herbal Medicine, Hochu-ekki-to, on Immunosuppression Induced by Surgical Stress. (2007)
  • Author(s): Kimura M, Sasada S, Kanai M, Kawai Y, Yoshida Y, Hayashi E, Iwata S, Takabayashi A.
  • Journal Title: Surgery Today. inpress(inpress)
  • NAID: 10021284484
• [Journal Article] Intra-arterial continuous infusion chemotherapy with 5-fluorouracil and cisplatin improves the prognosis of locally advanced pancreatic cancer patients. (2007)
  • Author(s): Sasada T, Denno R, Tanaka T, Kanai M, Mizukami Y, Kohno S, Takabayashi A.
  • Journal Title: Annual of Surgical Oncology. inpress(inpress)
• [Journal Article] SMAD4-deficient intestinal trmors recruit CCR1+ myeloid cells that promote invasion. (2007)
  • Author(s): Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H, Hosogi H, Aoki M, Oshima M, Hattori M, Takabayashi A, Minato N, Taketo MM.
  • Journal Title: Nature Genetics. 39(4) Pages: 467-475
• [Journal Article] 膵管出血をきたした退形成性膵管癌の1例 (2007)
  • Author(s): 水上陽, 笹田哲朗, 橋田裕毅, 水本明良, 佐藤正人, 上田修吾, 田中基文, 郡司周太郎, 大石賢玄, 小山幸法, 吉田昌弘, 金井陸行, 鷹巣晃昌, 高林有道.
  • Journal Title: 膵臓. 22(4)(inpress)
  • NAID: 10024366572
• [Journal Article] Acute cerebral infarction during combination chemotherapy with s-1 and cisplatin for a young patient with a mucin-producing adenocarcinoma of the stomach. (2006)
  • Author(s): Ohashi S, Yazumi S, Nishio A, Fukui T, Asada M, Chiba T
  • Journal Title: Internal Medicine. 45(18) Pages: 1049-1053
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production. (2006)
  • Author(s): Tamaki H, Nakamura H, Nishio A, Nakase H, Ueno S, Uza N, Kido M, Inoue S, Mikami S, Asada M, Kiriya K, Kitamura H, Ohashi S, Fukui T, Kawasaki K, Matsuura M, Ishii Y, Okazaki K, Yodoi J, Chiba T
  • Journal Title: Gastroenterology. 131(4) Pages: 1110-1121
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice. (2006)
  • Author(s): Ohashi S, Nishio A, Nakamura H, Asada M, Tamaki H, Kawasaki K, Fukui T, Yodoi J, Chiba T
  • Journal Title: Antioxid Redox Signal. 8(9-10) Pages: 1835-1845
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Education and imaging. Gastrointestinal : epidermal metaplasia of the esophagus. (2006)
  • Author(s): Fukui T, Sakurai T, Miyamoto S, Ueno S, Kido M, Kiriya K, Inoue S, Ohashi S, Nishio A, Chiba T
  • Journal Title: Journal of Gastroenterology and Hepatology 21(10) Pages: 1627-1627
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• [Journal Article] Education and imaging. Gastrointestinal : MALT lymphoma of the terminal ileum. (2006)
  • Author(s): Ohashi S, Yazumi S, Watanabe N, Matsumoto S, Fukui T, Nishio A, Chiba T
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• [Journal Article] Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. (2006)
  • Author(s): Asada M, Nishio A, Uchida K, Kido M, Ueno S, Uza N, Kiriya K, Inoue S, Kitamura H, Ohashi S, Tamaki H, Fukui T, Matsuura M, Kawasaki K, Nishi T, Watanabe N, Nakase H, Chiba T, Okazaki K
  • Journal Title: Pancreas. 33(1) Pages: 20-26
  • NAID: 10024366307
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinical significance of serum thioredoxin 1 levels in patients with acute pancreatitis. (2006)
  • Author(s): Ohashi S, Nishio A, Nakamura H, Kido M, Kiriya K, Asada M, Tamaki H, Fukui T, Kawasaki K, Watanabe N, Yodoi J, Okazaki K, Chiba T
  • Journal Title: Pancreas. 32(3) Pages: 264-270
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Acute cerebral infarction during combination chemotherapy with s-1 and cisplatin for a young patient with a mucin- producing adenocarcinoma of the stomach. (2006)
  • Author(s): Ohashi S, Yazumi S, Nishio A, Fukui T, Asada M, Chiba T.
  • Journal Title: Internal Medicine 45(18) Pages: 1049-1053
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production. (2006)
  • Author(s): Tamaki H, Nakamura H, Nishio A, Nakase H, Ueno S, Uza N, Kido M, Inoue S, Mikami S, Asada M, Kiriya K, Kitamura H, Ohashi S, Fukui T, Kawasaki K, Matsuura M, Ishii Y, Okazaki K, Yodoi J, Chiba T.
  • Journal Title: Gastroenterology 131(4) Pages: 1110-1121
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice. (2006)
  • Author(s): Ohashi S, Nishio A, Nakamura H, Asada M, Tamaki H, Kawasaki K, Fukui T, Yodoi J, Chiba T.
  • Journal Title: Antioxid Redox Signal 8(9-10) Pages: 1835-45
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Education and imaging. Gastrointestinal : epidermal metaplasia of the esophagus. (2006)
  • Author(s): Fukui T, Sakurai T, Miyamoto S, Ueno S, Kido M, Kiriya K, Inoue S, Ohashi S, Nishio A, Chiba T.
  • Journal Title: Journal of Gastroenterology and Hepatology 8(9-10) Pages: 1627-1627
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Education and imaging. Gastrointestinal : MALT lymphoma of the terminal ileum. (2006)
  • Author(s): Ohashi S, Yazumi S, Watanabe N, Matsumoto S, Fukui T, Nishio A, Chiba T.
  • Journal Title: Journal of Gastroenterology and Hepatology 21(9) Pages: 1495-1495
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. (2006)
  • Author(s): Asada M, Nishio A, Uchida K, Kido M, Ueno S, Uza N, Kiriya K, Inoue S, Kitamura H, Ohashi S, Tamaki H, Fukui T, Matsuura M, Kawasaki K, Nishi T, Watanabe N, Nakase H, Chiba T, Okazaki K.
  • Journal Title: Pancreas. 33(1) Pages: 20-26
  • NAID: 10024366307
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical significance of serum thioredoxin 1 levels in patients with acute pancreatitis. (2006)
  • Author(s): Ohashi S, Nishio A, Nakamura H, Kido M, Kiriya K, Asada M, Tamaki H, Fukui T, Kawasaki K, Watanabe N, Yodoi J, Okazaki K, Chiba T.
  • Journal Title: Pancreas. 32(3) Pages: 264-70
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acute cerebral infarction during combination chemotherapy with s-1 and cisplatin for a young patient with a mucin-producing adenocarcinoma of the stomach. (2006)
  • Author(s): Ohashi S, Yazumi S, Nishio A, Fukui T, Asada M, Chiba T.
  • Journal Title: Internal Medicine. 45(18) Pages: 1049-1053
• [Journal Article] Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production. (2006)
  • Author(s): Tamaki H, Nakamura H, Nishio A, Nakase H, Ueno S, Uza N, Kido M, Inoue S, Mikami S, Asada M, Kiriya K Kitamura H, Ohashi S, Fukui T, Kawasahi KMatsuura M, Isii Y, Okazaki K YodoiJ, Chiba T.
  • Journal Title: Gastroenterology. 131(4) Pages: 1110-1121
• [Journal Article] Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice. (2006)
  • Author(s): Ohashi S, Nishio A, Nakamura H, Asada M, Tamaki H, Kawasaki K, Fukui T, Yodoi J, Chiba T.
  • Journal Title: Antioxid Redox Signal. 8(9-10) Pages: 1835-1845
• [Journal Article] Education and imaging. Gastrointestinal : epidermal metaplasia of the esophagus. (2006)
  • Author(s): Fukui T, Sakurai T, Miyamoto S, Ueno S, Kido M, Kiriya K, Inoue S, Ohashi S, Nishio A, Chiba T.
  • Journal Title: Journal of Gastroenterology and Hepatology 21(10) Pages: 1627-1627
• [Journal Article] Education and imaging. Gastrointestinal : MALT lymphoma of the terminal ileum. (2006)
  • Author(s): Ohashi S, Yazumi S, Watanabe N, Matsumoto S, Fukui T, Nishio A, Chiba T.
  • Journal Title: Journal of Gastroenterology and Hepatology. 21(9) Pages: 1495-1495
• [Journal Article] Clinical significance of serum thioredoxin 1 levels in patients with acute pancreatitis. (2006)
  • Author(s): Ohashi S, Nishio A, Nakamura H, Kido M, Kiriya K, Asada M, Tamaki H, Fukui T, Kawasaki K, Watanabe N, Yodoi J, Okazaki K, Chiba T.
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