Development of the new therapy using glucagon like peptide -2 for the necrotising enterocolitis

• Project/Area Number: 16K10094
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Kagoshima University
• Principal Investigator: Kazuhiko Nakame 鹿児島大学, 医歯学域附属病院, 講師 (70448570)
• Co-Investigator(Kenkyū-buntansha): 家入 里志 鹿児島大学, 医歯学域医学系, 教授 (00363359) ; 谷本 昭英 鹿児島大学, 医歯学域医学系, 教授 (10217151) ; 山田 和歌 鹿児島大学, 医歯学域附属病院, 特任助教 (20457659) ; 川野 孝文 鹿児島大学, 医歯学総合研究科, 客員研究員 (40457651) ; 加治 建 鹿児島大学, 附属病院, 特任教授 (50315420) ; 向井 基 鹿児島大学, 医歯学域医学系, 准教授 (80468024) ; 山田 耕嗣 鹿児島大学, 附属病院, 医員 (80528042) ; 大西 峻 鹿児島大学, 附属病院, 医員 (10614638)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 壊死性腸炎 / 新生児 / 低出生体重児 / サイトカイン / 予防 / GLP-2 / 炎症性サイトカイン / ＧＬＰ－２ / ラット / 治療

Outline of Final Research Achievements

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease, that affects premature infants. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic hormone and reduces the inflammation. We suspected that GLP-2 would have protective and anti-inflammatory effects in an experimental rat model of NEC. NEC was induced in newborn rats by enteral feeding with hyperosmolar formula, asphyxial stress and enteral administration of lipopolysaccharide (LPS). Rats were randomly divided into the following four groups: dam-fed, NEC, NEC+GLP-2(low dose), and NEC+GLP-2(high dose). The NEC score and the survival rate in the NEC+GLP-2(H) group was improved compared with those in the NEC and the NEC+GLP-2(L) groups. High dose GLP-2 administration improved the incidence and survival rate for NEC. It also decreased ileal mucosal inflammatory cytokine production. These results support a potential therapeutic role for GLP-2 in the treatment of NEC.

Academic Significance and Societal Importance of the Research Achievements

壊死性腸炎は新生児、特に低出生体重児に発症する腸管の壊死を伴う腸管不全であり、高率な死亡率(約40%)を有する疾患である。近年、早産児、低出生体重児の出生数が増加しており、それに伴い生存率を高めるだけでなく、intact survival(後遺症なき生存)が目指されている。一方、グルカゴンライクペプチドー２(GLP-2)は腸管に対する成長因子、抗炎症作用を有するペプチドであり、短腸症候群・炎症性腸疾患への臨床応用が期待されている。現在、日本でも短腸症候群に対して臨床試験が進行している。当研究は壊死性腸炎ラットモデルを用いてGLP-2の治療効果を証明した。壊死性腸炎への臨床応用が期待される。

Research Products

• [Journal Article] Three Cases of Pyriform Sinus Fistula Presenting With Respiratory Distress in the Neonatal Period and a Review of the Literature in Japan (2018)
  • Author(s): 中目 和彦、家入 里志、山田 耕嗣、山田 和歌、桝屋 隆太、川野 孝文、町頭 成郎、向井 基、加治 建、野口 啓幸
  • Journal Title: Journal of the Japanese Society of Pediatric Surgeons Volume: 54 Issue: 5 Pages: 1117-1123
  • DOI: 10.11164/jjsps.54.5_1117
  • NAID: 130007437292
  • ISSN: 0288-609X, 2187-4247
  • Year and Date: 2018-08-20
  • Peer Reviewed / Open Access
• [Journal Article] A rare case of ectopic pancreas presenting with persistent umbilical discharge (2018)
  • Author(s): Nakame K, Hamada R, Suzuhigashi M, Nanashima A, Ieiri S
  • Journal Title: Pediatrics International Volume: 60 Issue: 9 Pages: 891-892
  • DOI: 10.1111/ped.13637
  • Peer Reviewed / Open Access
• [Journal Article] Long-term outcomes of surgery for choledochal cysts: a single-institution study focusing on follow-up and late complications (2018)
  • Author(s): Mukai Motoi、Kaji Tatsuru、Masuya Ryuta、Yamada Koji、Sugita Koshiro、Moriguchi Tomoe、Onishi Shun、Yamada Waka、Kawano Takafumi、Machigashira Seiro、Nakame Kazuhiko、Takamatsu Hideo、Ieiri Satoshi
  • Journal Title: Surgery Today Volume: 48 Issue: 9 Pages: 835-840
  • DOI: 10.1007/s00595-018-1660-9
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin Stimulates Intestinal Adaptation Following Massive Small Bowel Resection (2018)
  • Author(s): Onishi S, Kaji T, Yamada W, Nakame K, Machigashira S, Yano K, Kawano M, Harumatsu T,Masuya R, Kawano T, Mukai M, Yoshioka T, Souda M, Hamada T, Tanimoto A, Ieiri S
  • Journal Title: Peptide Volume: 106 Pages: 264-267
  • DOI: 10.1016/j.peptides.2018.06.009
  • Peer Reviewed / Open Access
• [Journal Article] The effect of intravenous lipid emulsions and mucosal adaptation following massive bowel resection (2018)
  • Author(s): Onishi Shun、Kaji Tatsuru、Machigashira Seiro、Yamada Waka、Masuya Ryuta、Nakame Kazuhiko、Kawano Masato、Yano Keisuke、Yamada Koji、Kawano Takafumi、Mukai Motoi、Yoshioka Takako、Tanimoto Akihide、Ieiri Satoshi
  • Journal Title: Journal of Pediatric Surgery Volume: 53 Issue: 12 Pages: 2444-2448
  • DOI: 10.1016/j.jpedsurg.2018.08.019
  • Peer Reviewed / Open Access
• [Journal Article] Mediastinal mature teratoma causing cardiac tamponade—A pediatric case report (2018)
  • Author(s): 中目 和彦、岡本 康裕、加治 建、河野 嘉文、家入 里志、山田 和歌、川野 孝文、町頭 成郎、上野 健太郎、西川 拓朗、田邊 貴幸、向井 基、義岡 孝子
  • Journal Title: The Japanese Journal of Pediatric Hematology / Oncology Volume: 55 Issue: 5 Pages: 427-431
  • DOI: 10.11412/jspho.55.427
  • NAID: 130007580407
  • ISSN: 2187-011X, 2189-5384
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of a successful outcome for infants with short bowel syndrome: a 30-year single-institution experience (2017)
  • Author(s): Kaji Tatsuru、Nakame Kazuhiko、Machigashira Seiro、Kawano Takafumi、Masuya Ryuta、Yamada Waka、Yamada Koji、Onishi Shun、Moriguchi Tomoe、Sugita Koshiro、Mukai Motoi、Ieiri Satoshi
  • Journal Title: Surgery Today Volume: 47 Issue: 11 Pages: 1391-1396
  • DOI: 10.1007/s00595-017-1534-6
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel variant of the RET proto-oncogene in a novel family with Hirschsprung’s disease (2017)
  • Author(s): Kawano Takafumi、Hosomichi Kazuyoshi、Inoue Ituro、Shimono Ryuichi、Onishi Shun、Nakame Kazuhiko、Kaji Tatsuru、Matsufuji Hiroshi、Ieiri Satoshi
  • Journal Title: Pediatric Surgery International Volume: 33 Issue: 10 Pages: 1041-1046
  • DOI: 10.1007/s00383-017-4134-z
  • Peer Reviewed / Open Access
• [Journal Article] Current characteristics and management of congenital esophageal stenosis: 40 consecutive cases from a multicenter study in the Kyushu area of Japan (2017)
  • Author(s): Suzuhigashi Masaya、Kaji Tatsuru、Noguchi Hiroyuki、Muto Mitsuru、Goto Michiko、Mukai Motoi、Nakame Kazuhiko、Kawano Takafumi、Yamada Waka、Yamada Koji、Onishi Shun、Ieiri Satoshi
  • Journal Title: Pediatric Surgery International Volume: 33 Issue: 10 Pages: 1035-1040
  • DOI: 10.1007/s00383-017-4133-0
  • Peer Reviewed / Open Access
• [Journal Article] The novel preventive effect of Daikenchuto (TJ-100), a Japanese herbal drug, against neonatal necrotizing enterocolitis in rats (2017)
  • Author(s): Shinyama Shin、Kaji Tatsuru、Mukai Motoi、Nakame Kazuhiko、Matsufuji Hiroshi、Takamatsu Hideo、Ieiri Satoshi
  • Journal Title: Pediatric Surgery International Volume: 33 Issue: 10 Pages: 1109-1114
  • DOI: 10.1007/s00383-017-4145-9
  • Peer Reviewed / Open Access
• [Journal Article] A comparison of the characteristics and precision of needle driving for right-handed pediatric surgeons between right and left driving using a model of infant laparoscopic diaphragmatic hernia repair (2017)
  • Author(s): Ikee Takamasa、Onishi Shun、Mukai Motoi、Kawano Takafumi、Sugita Koshiro、Moriguchi Tomoe、Yamada Koji、Yamada Waka、Masuya Ryuta、Machigashira Seiro、Nakame Kazuhiko、Kaji Tatsuru、Ieiri Satoshi
  • Journal Title: Pediatric Surgery International Volume: 33 Issue: 10 Pages: 1103-1108
  • DOI: 10.1007/s00383-017-4144-x
  • Peer Reviewed / Open Access
• [Journal Article] The bowel function and quality of life of Hirschsprung disease patients who have reached 18 years of age or older ? the long-term outcomes after undergoing the transabdominal soave procedure (2017)
  • Author(s): Onishi Shun、Nakame Kazuhiko、Kaji Tatsuru、Kawano Masato、Moriguchi Tomoe、Sugita Koshiro、Yano Keisuke、Nomura Mioko、Yamada Koji、Yamada Waka、Masuya Ryuta、Kawano Takafumi、Machigashira Seiro、Mukai Motoi、Ieiri Satoshi
  • Journal Title: Journal of Pediatric Surgery Volume: 52 Issue: 12 Pages: 2001-2005
  • DOI: 10.1016/j.jpedsurg.2017.08.036
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin Improves Intestinal Mucosal Atrophy During Parenteral Nutrition: An Experimental Study (2016)
  • Author(s): Yamada W, Kaji T, Onishi S, Nakame K, Yamada K, Kawano T, Mukai M, Souda M, Yoshioka T, Tanimoto A, Ieiri S
  • Journal Title: J Pediatr Surg Volume: 51(12) Issue: 12 Pages: 2039-2043
  • DOI: 10.1016/j.jpedsurg.2016.09.035
  • Peer Reviewed / Open Access
• [Journal Article] Long-term outcome of bowel function for 110 consecutive cases of Hirschsprung's disease: Comparison of the abdominal approach with transanal approach over 30 years in a single institution : Is the transanal approach truly beneficial for bowel function? (2016)
  • Author(s): Onishi S, Nakame K, Yamada K, Yamada W, Kawano T, Mukai M, Kaji T, Ieiri S
  • Journal Title: J Pediatr Surg Volume: 51(12) Issue: 12 Pages: 2010-2014
  • DOI: 10.1016/j.jpedsurg.2016.09.029
  • Peer Reviewed / Open Access
• [Journal Article] Changing Profile of Safe Techniques for Insertion a Central Venous Catheter in Pediatric Patients - Improvement in Outcomes with the Experience of 500 Insertions in a Single Institution (2016)
  • Author(s): Kaji T, Kawano T, Yamada W, Yamada K, Onishi S, Nakame K, Mukai M, Ieiri S, Takamatsu H
  • Journal Title: J Pediatr Surg Volume: 51 Issue: 12 Pages: 2044-2047
  • DOI: 10.1016/j.jpedsurg.2016.09.037
  • Peer Reviewed / Open Access
• [Journal Article] The administration of ghrelin improved hepatocellular injury following parenteral feeding in a rat model of short bowel syndrome. (2016)
  • Author(s): Onishi S, Kaji T, Yamada Y, Moriguchi T, Sugita K, Yamada K, Kawano T, Nakame K, Mukai M, Yamada S, Yoshioka T, Tanimoto A, Ieiri S
  • Journal Title: Pediatr Surg Int Volume: 32(12) Issue: 12 Pages: 1165-1171
  • DOI: 10.1007/s00383-016-3975-1
  • Peer Reviewed / Open Access
• [Presentation] The optimum timing and surgical strategy for congenital cystic lung disease based (2018)
  • Author(s): Nakame K, Murakami M, Yano K, Baba T, Harumatsu T, Onishi S, Yamada K, Yamada W,Masuya R,Kawano T, Machigashira S, Mukai M, Kaji T, Ieiri S
  • Organizer: 20th Congress, The Federation of Asia and Oceania Perinatal Societies
  • Int'l Joint Research
• [Presentation] 40例の経験からみた先天性嚢胞性肺疾患の外科治療の検討―胸腔鏡手術時代の出生前診断例に対す (2018)
  • Author(s): 中目和彦, 矢野圭輔, 大西 峻, 山田耕嗣, 山田和歌, 桝屋隆太, 川野孝文, 町頭成郎, 向井 基,加治 建, 家入里志
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 40例の経験からみた先天性嚢胞性肺疾患の外科治療の検討―出生前診断例に対する治療戦略― (2018)
  • Author(s): 中目和彦, 川野正人, 矢野圭輔, 村上雅一, 馬場徳朗, 大西 峻, 春松敏夫, 山田耕嗣, 山田和歌,桝屋隆太, 川野孝文, 町頭成郎, 向井 基, 加治 建, 家入里志
  • Organizer: 第55回日本小児外科学会学術集会
• [Presentation] 新生児上気道狭窄に対する関連診療科との連携による治療戦略 (2018)
  • Author(s): 中目和彦, 矢野圭輔, 川野正人, 大西 峻, 山田耕嗣, 山田和歌, 桝屋隆太, 町頭成郎, 川野孝文,向井 基, 加治 建, 家入里志
  • Organizer: 第54回日本周産期・新生児医学会学術集会
• [Presentation] 気道外科専門外来開始後の初期導入効果に関する検討―地方小児外科拠点病院における気道外科疾患に対する取り組みー (2018)
  • Author(s): 中目和彦, 連 利博, 村上雅一, 矢野圭輔, 馬場徳朗, 春松敏夫, 大西 峻, 山田耕嗣,山田和歌, 桝屋隆太, 川野孝文, 町頭成郎, 向井 基 ,加治 建, 家入里志
  • Organizer: 第29回日本小児呼吸器外科研究会
• [Presentation] Nuss法による胸骨挙上術の治療成績と合併症の検討 (2018)
  • Author(s): 中目和彦, 村上雅一, 矢野圭輔, 大西 峻, 春松敏夫, 馬場徳朗, 山田耕嗣, 山田和歌,桝屋隆太, 町頭成郎, 向井 基, 加治 建, 家入里志
  • Organizer: 第18回Nuss法漏斗胸手術手技研究会
• [Presentation] Vascular anomalyに対する治療戦略-40例 の治療経験からみた外科治療の再評価-. (2017)
  • Author(s): 32.中目和彦、杉田光士郎, 森口智江, 大西 峻, 山田耕嗣, 山田和歌,桝屋隆太, 川野孝文, 町頭成郎,向井 基, 加治 建, 家入里志
  • Organizer: 第54回日本小児外科学会学術集会
• [Presentation] The operative results and the outcomes of treatment for abdominal wall defects- A 30-year single institution experience. (2016)
  • Author(s): Nakame K
  • Organizer: 19th Congress of the Federation of Asia and Oceania Perinatal Societies (FAOPS 2016) held
  • Place of Presentation: Taipei(Taiwan)
  • Year and Date: 2016-12-01
  • Int'l Joint Research
• [Presentation] 当科における胆道閉鎖術後自己肝生存率に対する予後因子の検討 (2016)
  • Author(s): 中目和彦
  • Organizer: 第53回日本小児外科学会学術集会（JSPS2016）
  • Place of Presentation: ヒルトン福岡シーホーク（福岡県・福岡市）
  • Year and Date: 2016-05-24