The development of drug delivery system of carbon monoxide for inflammatory bowel disease

• Project/Area Number: 16K09322
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Takagi Tomohisa 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (70405257)
• Co-Investigator(Kenkyū-buntansha): 内藤 裕二 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (00305575) ; 内山 和彦 京都府立医科大学, 医学(系)研究科(研究院), 助教 (50298428) ; 堅田 和弘 京都府立医科大学, 医学(系)研究科(研究院), 助教 (60593910)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Heme oxygenase-1 / 一酸化炭素 / 炎症性腸疾患 / Heme oxygenase / 腸管炎症 / マクロファージ / heme oxygenase-1 / ナイーブCD4+ T細胞 / Th17リンパ球分化 / ヘムオキシゲナーゼ / リンパ球分化

Outline of Final Research Achievements

In this project, we confirmed that heme oxygenase-1 (HO-1) is mainly expressed in macrophages in the inflamed colonic mucosa using the murine colitis model, and carbon monoxide (CO) produced from HO-1 directly regulates Th17 differentiation of lymphocytes, and CO regulated the gut environment by augmenting clearance of enteric microbes. In addition, the rectal administration of a CO-saturated solution protected the intestinal mucosa from inflammation and accelerated colonic ulcer healing through enhanced epithelial restoration. These data suggested that CO could be a novel therapeutic molecule in patients with inflammatory bowel disease, including ulcerative colitis and Crohn’s disease.

Academic Significance and Societal Importance of the Research Achievements

難治性・再発性疾患である炎症性腸疾患に対する病態解明・新規治療法の開発は重要な課題であり、本研究により抗酸化酵素HO-1(heme oxygenase-1)が抗原提示細胞（マクロファージ）に発現し、生成する一酸化炭素(carbon monoxide: CO)を介してリンパ球分化を制御し、一酸化炭素を介した免疫担当細胞間のシグナル架橋が存在することを示すことができた。また、COを治療分子とした新規治療法開発として、CO高含有溶解液作成が達成された。

Research Products

• [Int'l Joint Research] University of Wuerzburg(Germany)
• [Journal Article] Differences in gut microbiota associated with age, sex, and stool consistency in healthy Japanese subjects. (2019)
  • Author(s): Takagi T, Naito Y, Inoue R, Kashiwagi S, Uchiyama K, Mizushima K, Tsuchiya S, Dohi O, Yoshida N, Kamada K, Ishikawa T, Handa O, Konishi H, Okuda K, Tsujimoto Y, Ohnogi H, Itoh Y.
  • Journal Title: J Gastroenterol. Volume: 54 Issue: 1 Pages: 53-63
  • DOI: 10.1007/s00535-018-1488-5
  • Peer Reviewed
• [Journal Article] Elevated ER stress exacerbates dextran sulfate sodium-induced colitis in PRDX4-knockout mice (2019)
  • Author(s): Takagi T, Homma T, Fujii J, Shirasawa N, Yoriki H, Hotta Y, Higashimura Y, Mizushima K, Hirai Y, Katada K, Uchiyama K, Naito Y, Itoh Y.
  • Journal Title: Free Radical Biology and Medicine Volume: 134 Pages: 153-164
  • DOI: 10.1016/j.freeradbiomed.2018.12.024
  • Peer Reviewed
• [Journal Article] Heme oxygenase-1 prevents murine intestinal inflammation (2018)
  • Author(s): Takagi Tomohisa、Naito Yuji、Mizushima Katsura、Hirai Yasuko、Harusato Akihito、Okayama Tetsuya、Katada Kazhuhiro、Kamada Kazuhiro、Uchiyama Kazuhiko、Handa Osamu、Ishikawa Takeshi、Itoh Yoshito
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 63 Issue: 3 Pages: 169-174
  • DOI: 10.3164/jcbn.17-133
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] Carbon monoxide ameliorates murine T-cell dependent colitis through the inhibition of Th17 differentiation. (2018)
  • Author(s): Takagi T, Naito Y, Tanaka M, Mizushima K, Ushiroda C, Toyokawa Y, Uchiyama K, Hamaguchi M, Handa O, Itoh Y.
  • Journal Title: Free Radic Res Volume: 印刷中 Issue: 11-12 Pages: 1328-1335
  • DOI: 10.1080/10715762.2018.1470327
  • Peer Reviewed
• [Journal Article] Heme oxygenase-1 prevents murine intestinal inflammation (2018)
  • Author(s): Takagi T, Naito Y, Mizushima K, Hirai Y, Harusato A, Okayama T, Katada K, Kamada K, Uchiyama K, Handa O, Ishikawa T, Itoh Y.
  • Journal Title: J Clin Biochem Nutr. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] The influence of long-term use of proton pump inhibitors on the gut microbiota: an age-sex-matched case-control study (2018)
  • Author(s): Takagi T, Naito Y, Inoue R, Kashiwagi S, Uchiyama K, Mizushima K, Tsuchiya S, Okayama T, Dohi O, Yoshida N, Kamada K, Ishikawa T, Handa O, Konishi H, Okuda K, Tsujimoto Y, Ohnogi H, Itoh Y.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 62 Issue: 1 Pages: 100-105
  • DOI: 10.3164/jcbn.17-78
  • NAID: 130006301255
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] Secreted protein acidic and rich in cysteine functions in colitis via IL17A regulation in mucosal CD4(+) T cells. (2018)
  • Author(s): Tanaka M, Takagi T, Naito Y, Uchiyama K, Hotta Y, Toyokawa Y, Ushiroda C, Hirai Y, Aoi W, Higashimura Y, Mizushima K, Okayama T, Katada K, Kamada K, Ishikawa T, Handa O, Itoh Y.
  • Journal Title: J Gastroenterol Hepatol. Volume: 33 Issue: 3 Pages: 671-680
  • DOI: 10.1111/jgh.13842
  • Peer Reviewed / Open Access
• [Journal Article] Multiple targets of carbon monoxide gas in the intestinal inflammation. (2016)
  • Author(s): Naito Y, Takagi T, Uchiyama K, Katada K, Yoshikawa T.
  • Journal Title: Arch Biochem Biophys. Volume: 595 Pages: 147-52
  • DOI: 10.1016/j.abb.2015.06.020
  • Peer Reviewed / Open Access
• [Journal Article] Prevention of colitis by controlled oral drug delivery of carbon monoxide. (2016)
  • Author(s): Steiger C, Uchiyama K, Takagi T, Mizushima K, Higashimura Y, Gutmann M, Hermann C, Botov S, Schmalz HG, Naito Y, Meinel L.
  • Journal Title: J Control Release. Volume: 239 Pages: 128-36
  • DOI: 10.1016/j.jconrel.2016.08.030
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Carbon monoxide promotes gastric wound healing in mice via the protein kinase C pathway. (2016)
  • Author(s): Takagi T, Naito Y, Uchiyama K, Mizuhima K, Suzuki T, Horie R, Hirata I, Tsuboi H, Yoshikawa T.
  • Journal Title: Free Radic Res. Volume: 50(10) Pages: 1098-1105
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 腸管炎症病態における Heme oxygenase-1/Carbon monoxide系の 新規治療標的分子としての可能性 (2018)
  • Author(s): 髙木智久、内山和彦、豊川優季、東村泰希、 柏木里織、後田ちひろ、水島かつら、平井泰子、 鎌田和浩、石川剛、半田修、内藤裕二
  • Organizer: 第71回日本酸化ストレス学会学術集会
• [Presentation] Heme oxygenase-1 regulates the intestinal inflammation in murine colitis model (2018)
  • Author(s): Tomohisa Takagi, Yuji Naito, Katsura Mizushima, Yasuko Hirai, Kazuhiko Uchiyama, and Yoshito Itoh
  • Organizer: 10th International Symposium on Cell/ Tissue Injury and Cytoprotection/Organoprotection (ISCTICO)
  • Int'l Joint Research
• [Presentation] The role of heme oxygenase-1 in intestinal inflammation (2018)
  • Author(s): Tomohisa Takagi, Yuji Naito
  • Organizer: 10th International Conference of Heme Oxygenase
  • Int'l Joint Research / Invited
• [Presentation] Carbon monoxide promotes intestinal mucosal healing in colitis model (2016)
  • Author(s): Tomohisa Takagi, Yuji Naito, Kazuhiro Uchiyama, Yasuki Higashimura, Katsura Mizushima, Yohito Itoh
  • Organizer: 9TH International conference on Heme Oxygenase
  • Place of Presentation: Prague
  • Year and Date: 2016-09-14
  • Int'l Joint Research
• [Presentation] 腸管炎症病態におけるHeme oxygenase-1/Carbon monoxide系の役割 (2016)
  • Author(s): 髙木智久
  • Organizer: 第69回酸化ストレス学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-08-30
  • Invited
• [Patent(Industrial Property Rights)] 炎症性消化器官疾患用組成物 (2018)
  • Inventor(s): 髙木智久、内藤裕二、三浦かつら、坂上茂樹
  • Industrial Property Rights Holder: 京都府公立大学法人、住友精化株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-110688
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] 皮膚創傷用組成物 (2018)
  • Inventor(s): 髙木智久、浅井純、岡山哲也、三浦かつら、坂上茂樹
  • Industrial Property Rights Holder: 京都府公立大学法人、住友精化株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-110717
  • Filing Date: 2018