Evaluation of pharmaceutical HO-1 induction and mesenchymal stem cell combination therapy in meconium peritonitis mouse model

• Project/Area Number: 18K15710
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kobe University
• Principal Investigator: FUJIOKA KAZUMICHI 神戸大学, 医学部附属病院, 講師 (20568810)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 胎便性腹膜炎 / 炎症性疾患 / ヒト胎便 / 早産児マウス敗血症モデル / モデルマウス / 糞便懸濁液 / HO-1 / 間葉系幹細胞 / 胎便 / 胎便懸濁液 / 新生仔マウス / 新生児 / 炎症 / 細菌感染 / 動物モデル / 消化酵素 / 胎便性腹膜炎モデル / ヘムオキシゲナーゼ-1

Outline of Final Research Achievements

Background: Meconium peritonitis is caused by leakage of meconium into the fetal peritoneal cavity due to intestinal perforation. Objective: To generate a neonatal mouse model of meconium peritonitis via IP administration of human meconium suspension or “slurry” (MS) by applying the CS methodology. Methods: Fresh meconium was suspended in PBS to 500 mg/mL. 200 μL of MS (meconium) or PBS (control) was administered IP to 4d-old wild-type FVB mice pups. Body weight and survivals was monitored. Results: Administration of MS resulted in significant decreases in weight gain and survival (0.8±7.5% (n=26), and 58.8% (n=34), respectively) compared with PBS controls (18.6±4.8% (n=10) and 100% (n=10), respectively). Conclusions: IP administration of MS resulted in significant mortality and weight loss to 4d-old newborn pups, and affects blood gasses and electrolytes. Therefore, we conclude that this MS model can be used to study the pathophysiology and treatment of meconium peritonitis.

Academic Significance and Societal Importance of the Research Achievements

胎便性腹膜炎は、周産期の難治性疾患であり、胎生期の腸管穿孔により無菌性の胎便が腹腔内に漏出して生じる化学性腹膜炎と定義される。一方、その病態を反映する動物モデルが無く、有効な治療法もない。
本研究では、「胎便性腹膜炎の病態解明のための疾患モデル動物は確立できるか？」という学術的問いに解答するために、申請者の新生児モデルマウス作成技術を駆使し、胎便性腹膜炎モデルマウスを作製・解析し、新規治療法開発のための基盤を確立した。本モデルマウスの確立により、今後、薬物的ヘムオキシゲナーゼ-1誘導、間葉系幹細胞投与などの新規治療法の有効性の検討が可能となり、本研究成果の学術的意義は大きいと考えている。

Research Products

• [Journal Article] Recombinant human thrombomodulin attenuated sepsis severity in a non-surgical preterm mouse model (2020)
  • Author(s): Ashina Mariko、Fujioka Kazumichi、Nishida Kosuke、Okubo Saki、Ikuta Toshihiko、Shinohara Masakazu、Iijima Kazumoto
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 333-333
  • DOI: 10.1038/s41598-019-57265-2
  • NAID: 120006877475
  • Peer Reviewed / Open Access
• [Journal Article] Case report of eight pregnant women with syphilis. (2020)
  • Author(s): Nakasuji Y, Tanimura K, Sasagawa Y, Imafuku H, Morizane M, Fujioka K, Ohji G, Yamada H.
  • Journal Title: J Infect Chemother. Volume: 26(3) Issue: 3 Pages: 298-300
  • DOI: 10.1016/j.jiac.2019.10.016
  • NAID: 120006886619
  • Peer Reviewed
• [Journal Article] Insulin Therapy for Hyperglycemia in Neonatal Sepsis Using a Preterm Mouse Model (2019)
  • Author(s): Miyauchi Harunori、Fujioka Kazumichi、Okubo Saki、Nishida Kosuke、Ashina Mariko、Ikuta Toshihiko、Okata Yuichi、Maeda Kosaku、Iijima Kazumoto、Bitoh Yuko
  • Journal Title: Pediatrics International Volume: - Issue: 5 Pages: 581-586
  • DOI: 10.1111/ped.14126
  • NAID: 120006864552
  • Peer Reviewed / Open Access
• [Journal Article] Clinical factors associated with congenital cytomegalovirus infection: A cohort study of pregnant women and newborns. (2019)
  • Author(s): Uchida A, Tanimura K, Morizane M, Fujioka K, Morioka I, Oohashi M, Minematsu T, Yamada H.
  • Journal Title: Clin Infect Dis. Volume: Epub Issue: 11 Pages: 2833-2839
  • DOI: 10.1093/cid/ciz1156
  • NAID: 120006975760
  • Peer Reviewed
• [Journal Article] Pharmacokinetic assessment of alprazolam-induced neonatal abstinence syndrome using physiologically based pharmacokinetic model (2019)
  • Author(s): Yamamoto Kazuhiro、Fukushima Sachiyo、Mishima Yui、Hashimoto Mari、Yamakawa Kei、Fujioka Kazumichi、Iijima Kazumoto、Yano Ikuko
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 34 Issue: 6 Pages: 400-402
  • DOI: 10.1016/j.dmpk.2019.09.002
  • NAID: 120006775971
  • Peer Reviewed
• [Journal Article] Incidence and Neonatal Risk factors of Short Stature and Growth Hormone treatment in Japanese Preterm Infants Born Small for Gestational Age. (2019)
  • Author(s): Matsumoto M, Nagano N, Awano H, Ohyama S, Fujioka K, Iwatani S, Urakami T, Iijima K, Morioka I.
  • Journal Title: Sci Rep. Volume: 9(1) Issue: 1 Pages: 12238-12238
  • DOI: 10.1038/s41598-019-48785-y
  • NAID: 120006719426
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic Value of Cytomegalovirus IgM Antibodies at Birth in PCR-Confirmed Congenital Cytomegalovirus Infection (2019)
  • Author(s): Ohyama Shohei、Fujioka Kazumichi、Fukushima Sachiyo、Abe Shinya、Ashina Mariko、Ikuta Toshihiko、Nishida Kosuke、Matsumoto Hisayuki、Nakamachi Yuji、Tanimura Kenji、Yamada Hideto、Iijima Kazumoto
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 13 Pages: 3239-3239
  • DOI: 10.3390/ijms20133239
  • NAID: 120006712319
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of poor neurological development in patients with symptomatic congenital cytomegalovirus diseases after oral valganciclovir treatment (2019)
  • Author(s): Fukushima Sachiyo、Morioka Ichiro、Ohyama Shohei、Nishida Kosuke、Iwatani Sota、Fujioka Kazumichi、Mandai Tsurue、Matsumoto Hisayuki、Nakamachi Yuji、Deguchi Masashi、Tanimura Kenji、Iijima Kazumoto、Yamada Hideto
  • Journal Title: Brain and Development Volume: 41 Issue: 9 Pages: 743-750
  • DOI: 10.1016/j.braindev.2019.04.016
  • NAID: 120006782284
  • Peer Reviewed
• [Journal Article] Mesenchymal stem cell therapy for neonatal intraventricular hemorrhage: a long way to go? (2019)
  • Author(s): Abe S, Fujioka K.
  • Journal Title: Ann Transl Med. Volume: 7(5) Issue: 5 Pages: 79-79
  • DOI: 10.21037/atm.2018.12.69
  • NAID: 120006954844
  • Open Access
• [Journal Article] Efficacy of Valganciclovir Treatment Depends on the Severity of Hearing Dysfunction in Symptomatic Infants with Congenital Cytomegalovirus Infection (2019)
  • Author(s): Ohyama Shohei、Morioka Ichiro、Fukushima Sachiyo、Yamana Keiji、Nishida Kosuke、Iwatani Sota、Fujioka Kazumichi、Matsumoto Hisayuki、Imanishi Takamitsu、Nakamachi Yuji、Deguchi Masashi、Tanimura Kenji、Iijima Kazumoto、Yamada Hideto
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 6 Pages: 1388-1388
  • DOI: 10.3390/ijms20061388
  • NAID: 120006624227
  • Peer Reviewed / Open Access
• [Journal Article] DNA methylation of the Rtl1 promoter in the placentas with fetal growth restriction (2019)
  • Author(s): Fujioka Kazumichi、Nishida Kosuke、Ashina Mariko、Abe Shinya、Fukushima Sachiyo、Ikuta Toshihiko、Ohyama Shohei、Morioka Ichiro、Iijima Kazumoto
  • Journal Title: Pediatrics & Neonatology Volume: S1875-9572(18) Issue: 5 Pages: 30550-3
  • DOI: 10.1016/j.pedneo.2019.01.001
  • NAID: 120006733142
  • Peer Reviewed / Open Access
• [Journal Article] 生体侵襲とショックの基礎病態学、今 Cecal Slurry法を用いた早産児マウス敗血症モデルの利点と課題 (2019)
  • Author(s): 藤岡 一路
  • Journal Title: Shock: 日本Shock学会雑誌 Volume: 33巻2号 Pages: 28-33
• [Journal Article] Hydrogen ventilation combined with mild hypothermia improves short-term neurological outcomes in a 5-day neonatal hypoxia-ischaemia piglet model (2019)
  • Author(s): Htun Yinmon、Nakamura Shinji、Nakao Yasuhiro、Mitsuie Tsutomu、Nakamura Makoto、Yamato Satoshi、Jinnai Wataru、Koyano Kosuke、Ohta Kenichi、Morimoto Aya、Wakabayashi Takayuki、Sugino Masashiro、Fujioka Kazumichi、Kato Ikuko、Kondo Sonoko、Yasuda Saneyuki、Miki Takanori、Ueno Masaki、Kusaka Takashi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 4088-4088
  • DOI: 10.1038/s41598-019-40674-8
  • NAID: 120006599245
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Isolation and Characterization of Human Umbilical Cord-derived Mesenchymal Stem Cells from Preterm and Term Infants (2019)
  • Author(s): Iwatani Sota、Yoshida Makiko、Yamana Keiji、Kurokawa Daisuke、Kuroda Jumpei、Thwin Khin Kyae Mon、Uemura Suguru、Takafuji Satoru、Nino Nanako、Koda Tsubasa、Mizobuchi Masami、Nishiyama Masahiro、Fujioka Kazumichi、Nagase Hiroaki、Morioka Ichiro、Iijima Kazumoto、Nishimura Noriyuki
  • Journal Title: Journal of Visualized Experiments Volume: 143 Issue: 143 Pages: 1-1
  • DOI: 10.3791/58806
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neonatal vitamin K deficiency in the son of a mother with short bowel syndrome (2018)
  • Author(s): Ashina Mariko、Fujioka Kazumichi、Nishida Kosuke、Iijima Kazumoto
  • Journal Title: Pediatrics International Volume: 60 Issue: 10 Pages: 991-992
  • DOI: 10.1111/ped.13684
  • Peer Reviewed
• [Journal Article] Feeding interval and use of donor breast milk for very low birthweight infants: A?nationwide survey in Japan (2018)
  • Author(s): Ashina Mariko、Fujioka Kazumichi、Totsu Satsuki、Shoji Hiromichi、Miyazawa Tokuo、Wada Kazuko、Iijima Kazumoto、Morioka Ichiro
  • Journal Title: Pediatrics & Neonatology Volume: S1875-9572(18) Issue: 3 Pages: 30235-3
  • DOI: 10.1016/j.pedneo.2018.07.006
  • NAID: 120006647361
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation index for asymmetric ventricular size on brain magnetic resonance images in very low birth weight infants (2018)
  • Author(s): Ikuta Toshihiko、Mizobuchi Masami、Katayama Yoshinori、Yoshimoto Seiji、Ioroi Tomoaki、Yamane Masayuki、Morisawa Takeshi、Takatera Akihiro、Ueda Masaaki、Shibata Akio、Maeyama Kaori、Mandai Tsurue、Fujioka Kazumichi、Nishimura Noriyuki、Iijima Kazumoto、Morioka Ichiro
  • Journal Title: Brain and Development Volume: 40 Issue: 9 Pages: 753-759
  • DOI: 10.1016/j.braindev.2018.05.007
  • NAID: 120006873025
  • Peer Reviewed
• [Journal Article] Hepatitis B vaccine: Immunogenicity in an extremely low-birthweight infant (2018)
  • Author(s): Yamana Keiji、Iwatani Sota、Fujioka Kazumichi、Iijima Kazumoto、Morioka Ichiro
  • Journal Title: Pediatrics International Volume: 60 Issue: 5 Pages: 489-490
  • DOI: 10.1111/ped.13547
  • NAID: 120006873024
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth. (2018)
  • Author(s): Rappoport N, Toung J, Hadley D, Wong RJ, Fujioka K, Jelliffe-Pawlowski LL, Gould JB, Darmstadt GL, Wang X, Bustamante CD, Snyder MP, Ziv E, Patsopoulos NA, Muglia LJ, Burchard E, Shaw GM, O'Brodovich HM, Stevenson DK, Butte AJ, Sirota M, et al.
  • Journal Title: Sci Rep. Volume: 8(1) Issue: 1 Pages: 226-226
  • DOI: 10.1038/s41598-017-18246-5
  • NAID: 120006599244
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ヒト胎便懸濁液の腹腔内投与による胎便性腹膜炎モデルマウスと早産児マウス敗血症モデルの比較 (2019)
  • Author(s): 芦名 満理子, 藤岡 一路, 仲宗根 瑠花, 永井 貞之, 菅 秀太郎, 阿部 真也, 福嶋 祥代, 大山 正平, 生田 寿彦, 西田 浩輔, 飯島 一誠
  • Organizer: 日本新生児成育医学会
• [Presentation] ヒト胎便懸濁液の腹腔内投与による胎便性腹膜炎モデルマウスの作成 (2019)
  • Author(s): 芦名 満理子, 宮内 玄徳, 西田 浩輔, 藤岡 一路
  • Organizer: 日本Shock学会
• [Presentation] モデルマウス及び患者検体を用いた胎便性腹膜炎の病態解明と新規治療法の開発 (2019)
  • Author(s): 藤岡 一路, 芦名 満理子, 宮内 玄徳
  • Organizer: 日本小児科学会
• [Presentation] ヒト胎便懸濁液の腹腔内投与による胎便性腹膜炎モデルマウス作成の試み (2019)
  • Author(s): 藤岡 一路, 芦名 満理子, 宮内 玄徳, 阿部 真也, 福嶋 祥代, 大山 正平, 生田 寿彦, 西田 浩輔, 飯島 一誠
  • Organizer: 日本周産期・新生児医学会
• [Presentation] Cecal Slurry法を用いて作成した新生児腹膜炎性敗血症モデルマウスに対するインスリン療法の保護効果の検討 (2019)
  • Author(s): 宮内 玄徳, 藤岡 一路, 大片 祐一, 尾藤 祐子, 會田 洋輔, 冨岡 雄一郎, 中谷 太一, 橘木 由美子, 中井 優美子
  • Organizer: 日本小児外科学会
• [Presentation] 新生児分野で臨床応用が期待される基礎研究 Cecal slurry法を用いた早産児マウス敗血症モデルの作成と臨床応用 (2018)
  • Author(s): 藤岡 一路
  • Organizer: 第121回日本小児科学会学術集会
• [Presentation] Cacel Slury法を用いた早産児マウス敗血症モデルの利点と課題 (2018)
  • Author(s): 藤岡 一路
  • Organizer: 第33回日本Shock学会総会
• [Presentation] 早産児マウス敗血症モデルにおける酸化ストレスの検討 (2018)
  • Author(s): 宮内 玄徳、芦名 満理子、西田 浩輔、藤岡 一路
  • Organizer: 第33回日本Shock学会総会
• [Presentation] 早産児マウス敗血症モデルにおける肝臓脂質メディエーター動態の検討 (2018)
  • Author(s): 芦名 満理子、西田 浩輔、藤岡 一路
  • Organizer: 第33回日本Shock学会総会
• [Presentation] 早産児マウス敗血症モデルを用いたストレス誘導性高血糖に対するインスリン療法の検討 (2018)
  • Author(s): 藤岡 一路、大久保 沙紀、芦名 満理子、生田 寿彦、宮内 玄徳、福嶋 祥代、大山 正平、山名 啓司、飯島 一誠、森岡 一朗
  • Organizer: 第 54 回日本周産期・新生児医学会学術集会
• [Presentation] 早産児マウス敗血症モデルにおける肝臓脂質メディエーター動態の検討 (2018)
  • Author(s): 芦名 満理子、大山 正平、宮内 玄徳、生田 寿彦、福嶋 祥代、大久保 沙紀、山名 啓司、藤岡 一路、飯島 一誠、森岡 一朗、篠原 正和
  • Organizer: 第 54 回日本周産期・新生児医学会学術集会
• [Presentation] 早産児マウス敗血症モデルにおける肝臓脂質メディエーター動態およびヒトリコンビナントトロンボモジュリンの保護効果の検討 (2018)
  • Author(s): 芦名 満理子、藤岡 一路、阿部 真也、福嶋 祥代、大山 正平、生田 寿彦、西田 浩輔、篠原 正和、飯島 一誠
  • Organizer: 第50回日本小児感染症学会総会・学術集会
• [Presentation] 早産児マウス敗血症モデルにおけるヒト免疫グロブリンおよび生理食塩水を用いた容量負荷の検 討 " (2018)
  • Author(s): 阿部 真也、藤岡 一路、芦名 満理子、福嶋 祥代、生田 寿彦、大山 正平、西田 浩輔、飯島 一誠
  • Organizer: 第63回日本新生児成育医学会・学術集会
• [Presentation] 早産児マウス敗血症モデルにおけるストレス誘導性高血糖と酸化ストレス動態の検討 (2018)
  • Author(s): 西田 浩輔、藤岡 一路、芦名 満理子、阿部 真也、福嶋 祥代、生田 寿彦、大山 正平、飯島 一誠
  • Organizer: 第63回日本新生児成育医学会・学術集会
• [Presentation] The protective role of trained immunity against lethal sepsis in neonatal mice (2018)
  • Author(s): Kazumichi Fujioka, Mariko Ashina, Shinya Abe, Sachiyo Fukushima, Toshihiko Ikuta, Shohei Ohyama, Kosuke Nishida, Kazumoto Iijima
  • Organizer: 第63回日本新生児成育医学会・学術集会
• [Presentation] 後方視的研究の手法（裏技！仮説無きデータ蓄積から始まる研究デザイン） (2018)
  • Author(s): 藤岡 一路
  • Organizer: 第63回日本新生児成育医学会・学術集会
• [Presentation] Insulin Therapy for Stress-Induced Hyperglycemia in Neonatal Sepsis Using A Preterm Mouse Model (2018)
  • Author(s): Kazumichi Fujioka, Saki Okubo, Kosuke Nishida, Mariko Ashina, Toshihiko Ikuta, Sachiyo Fukushima, Shohei Ohyama, Keiji Yamana, Ronald J. Wong, Kazumoto Iijima, Ichiro Morioka
  • Organizer: Pediatric Academic Society Annual Meeting
• [Presentation] The Effect of Recombinant Human Thrombomodulin (rh-TM) in Neonatal Sepsis Using a Preterm Mouse Model (2018)
  • Author(s): Kazumichi Fujioka, Kosuke Nishida, Saki Okubo, Mariko Ashina, Toshihiko Ikuta, Sachiyo Fukushima, Shohei Ohyama, Keiji Yamana, Ronald J. Wong, Kazumoto Iijima, Ichiro Morioka
  • Organizer: Pediatric Academic Society Annual Meeting
• [Presentation] Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model (2018)
  • Author(s): Kazumichi Fujioka, Kalish F, Zhao H, Wong RJ, Stevenson DK.
  • Organizer: The 2nd Korea-Japan-Taiwan Joint Congress on Neonatology
• [Presentation] The Protective Role of Trained Immunity against Lethal Sepsis in Neonatal Mice (2018)
  • Author(s): Kazumichi Fujioka, Mariko Ashina, Shinya Abe, Sachiyo Fukushima, Toshihiko Ikuta, Shohei Ohyama, Kosuke Nishida, Kazumoto Iijima
  • Organizer: The Federations of Asia and Oceania Perinatal Societies 2018
• [Presentation] Abnormal DNA methylation of Retrotransposon-like protein 1 gene in the placenta of severely small for gestational age infants (2018)
  • Author(s): Kazumichi Fujioka, Kosuke Nishida, Shinya Abe, Mariko Ashina, Sachiyo Fukushima, Toshihiko Ikuta, Shohei Ohyama, Kazumoto Iijima, Ichiro Morioka
  • Organizer: The 7th Congress of the European Academy of Paediatric Societies
• [Presentation] The protective role of trained immunity against lethal sepsis in neonatal mice (2018)
  • Author(s): Kazumichi Fujioka, Mariko Ashina, Shinya Abe, Sachiyo Fukushima, Toshihiko Ikuta, Shohei Ohyama, Kosuke Nishida, Kazumoto Iijima
  • Organizer: The 9th Asian Congress of Pediatric Infectious Diseases