Roles of bioactive lipids in regulation of lymphatic plasticity

• Project/Area Number: 26293055
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kitasato University
• Principal Investigator: Majima Masataka 北里大学, 医学部, 教授 (70181641)
• Co-Investigator(Kenkyū-buntansha): 藤田 朋恵 獨協医科大学, 医学部, 教授 (20296510) ; 天野 英樹 北里大学, 医学部, 講師 (60296481)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: prostaglandin / lymphatic / lymph node / edema / inflammation / metastasis / tumor / chemokine / premetastatic niche / COX-2 / SDF-1 / thromboxane / リンパ管新生 / LPS / TP受容体 / 横隔膜 / VEGF-C / Tリンパ球 / マクロファージ / リンパ管 / リンパ節 / 生理活性脂質 / 腫瘍 / 炎症 / リンパ節転移 / PG / 樹状細胞 / Treg / mPGES-1 / 慢性炎症 / 腹膜炎 / EP受容体 / VEGF / CD11b

Outline of Final Research Achievements

The lymphatic system is an important route for cancer dissemination, and lymph node metastasis (LNM) serves as a critical prognostic determinant in cancer patients. COX-2 is expressed in DCs from the early stage in the lymph node subcapsular regions, and COX-2 inhibition markedly suppressed mediastinal LNM. LNM was reduced in mice lacking the PGE2 receptor EP3. Accumulation of Tregs was also COX-2/EP3-dependent. To clarify the roles of cyclooxygenase (COX)-2 in enhancement of lymphangiogenesis during secondary lymphedema, we tested a mouse tail model and evaluated the recurrence of lymph flow. Lymphangiogenesis, together with recurrence of lymph flow after surgical induction of lymphedema, is upregulated by COX-2 possibly via generation of PGs. Lymphangiogenesis plays an important role in wound-healing. Lymphangiogenesis and recruitment of M2 macrophages that produced VEGF-C/D were suppressed in mice treated with a COX-2 inhibitor or lacking either EP3 or EP4 during wound healing.

Research Products

• [Journal Article] Inhibition of microsomal prostaglandin E synthase-1 facilitates liver repair after hepatic injury in mice. (2018)
  • Author(s): Nishizawa N, Ito Y, Eshima K, Ohkubo H, Kojo K, Inoue T, Raouf J, Jakobsson PJ, Uematsu S, Akira S, Narumiya S, Watanabe M, Majima M.
  • Journal Title: J Hepatol. Volume: S0168-8278(18) Issue: 1 Pages: 30126-30130
  • DOI: 10.1016/j.jhep.2018.02.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1+ cells from bone marrow (2017)
  • Author(s): Park Keiichi、Amano Hideki、Ito Yoshiya、Mastui Yoshio、Kamata Mariko、Yamazaki Yasuharu、Takeda Akira、Shibuya Masabumi、Majima Masataka
  • Journal Title: Anatomical Science International Volume: 印刷中 Issue: 3 Pages: 1-7
  • DOI: 10.1007/s12565-017-0424-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice (2017)
  • Author(s): Mishima Toshiaki、Ito Yoshiya、Nishizawa Nobuyuki、Amano Hideki、Tsujikawa Kazutake、Miyaji Kagami、Watanabe Masahiko、Majima Masataka
  • Journal Title: J Surg Res Volume: 219 Pages: 50-60
  • DOI: 10.1016/j.jss.2017.05.124
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Angiotensin II subtype 1a receptor signaling in resident hepatic macrophages induces liver metastasis formation (2017)
  • Author(s): Shimizu Yuki、Amano Hideki、Ito Yoshiya、Betto Tomohiro、Yamane Sakiko、Inoue Tomoyoshi、Nishizawa Nobuyuki、Matsui Yoshio、Kamata Mariko、Nakamura Masaki、Kitasato Hidero、Koizumi Wasaburo、Majima Masataka
  • Journal Title: Cancer Science Volume: 108 Issue: 9 Pages: 1757-1768
  • DOI: 10.1111/cas.13306
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostaglandin E Receptors, EP3 and EP4 Facilitates Wound Healing and Lymphangiogenesis with Enhanced Recruitment of M2 Macrophages in Mice. (2016)
  • Author(s): Hosono K, Isonaka R, Kawakami T, Narumiya S, Majima M.
  • Journal Title: PLoS One. Volume: 11 Issue: 10 Pages: e0162532-e0162532
  • DOI: 10.1371/journal.pone.0162532
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of lymphangiogenesis by soluble vascular endothelial growth factor receptor-2 in a mouse lung cancer model. (2016)
  • Author(s): Maehana S, Nakamura M, Ogawa F, Imai R, Murakami R, Kojima F, Majima M, Kitasato H.
  • Journal Title: Biomed Pharmacother. Volume: 84 Pages: 660-665
  • DOI: 10.1016/j.biopha.2016.09.083
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] RAMP1 suppresses mucosal injury from dextran sodium sulfate-induced colitis in mice. (2016)
  • Author(s): Kawashima-Takeda N, Ito Y, Nishizawa N, Kawashima R, Tanaka K, Tsujikawa K, Watanabe M, Majima M.
  • Journal Title: J Gastroenterol Hepatol. Volume: 32 Issue: 4 Pages: 809-818
  • DOI: 10.1111/jgh.13505
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Thromboxane A synthase enhances blood flow recovery from hindlimb ischemia. (2016)
  • Author(s): Amano H, Nakamura M, Ito Y, Kakutani H, Eshima K, Kitasato H, Narumiya S, Majima M.
  • Journal Title: J Surg Res. Volume: 204 Issue: 1 Pages: 153-163
  • DOI: 10.1016/j.jss.2016.04.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] BLT1 signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils (2016)
  • Author(s): Kojo, K., Ito, Y., Eshima, K., Nishizawa, N., Ohkubo, H., Yokomizo, T., Shimizu, T., Watanabe, M.,Majima, M.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 29650-29650
  • DOI: 10.1038/srep29650
  • Peer Reviewed / Open Access
• [Journal Article] Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages. (2016)
  • Author(s): Okizaki S, Ito Y, Hosono K, Oba K, Ohkubo H, Kojo K, Nishizawa N, Shibuya M, Shichiri M, Majima M.
  • Journal Title: Am J Pathol. Volume: 186 Pages: 1481-1498
  • DOI: 10.1016/j.biopha.2016.01.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune-mediated hepatitis. (2016)
  • Author(s): Fujita T, Soontrapa K, Ito Y, Iwaisako K, Moniaga CS, Asagiri M, Majima M, Narumiya S.
  • Journal Title: Hepatology Volume: 63 Issue: 4 Pages: 1325-1339
  • DOI: 10.1002/hep.28112
  • NAID: 120005663256
  • Peer Reviewed / Open Access
• [Journal Article] PDGFRα plays a crucial role in connective tissue remodeling. (2015)
  • Author(s): Horikawa S, Ishii Y, Hamashima T, Yamamoto S, Mori H, Fujimori T, Shen J, Inoue R, Nishizono H, Itoh H, Majima M, Abraham D, Miyawaki T, Sasahara M.
  • Journal Title: Scientific Reports Volume: Dec 7;5 Issue: 1 Pages: 17948-17948
  • DOI: 10.1038/srep17948
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of mPGES-1, an inducible prostaglandin E synthase, in enhancement of LPS-induced lymphangiogenesis in a mouse peritonitis model. (2015)
  • Author(s): Matsuda H, Hosono K, Tsuru S, Kurashige C, Sekiguchi K, Akira S, Uematsu S, Okamoto H, Majima M.
  • Journal Title: Life Sci. Volume: 142 Pages: 1-7
  • DOI: 10.1016/j.lfs.2015.10.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of cyclooxygenase-2 in the development of interstitial fibrosis in kidneys following unilateral ureteral obstruction in mice (2015)
  • Author(s): Kamata M, Hosono K, Fujita T, Kamata K, Majima M.
  • Journal Title: Biomed Pharmacother. Volume: 70 Pages: 174-180
  • DOI: 10.1016/j.biopha.2015.01.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppressed recruitment of alternatively activated macrophages reduces TGF-β1 and impairs wound healing in streptozotocin-induced diabetic mice. (2015)
  • Author(s): Okizaki S, Ito Y, Hosono K, Oba K, Ohkubo H, Amano H, Shichiri M, Majima M.
  • Journal Title: Biomed Pharmacother. Volume: 70 Pages: 317-325
  • DOI: 10.1016/j.biopha.2014.10.020
  • Peer Reviewed / Open Access
• [Journal Article] VEGFR1-positive macrophages facilitate liver repair and sinusoidal reconstruction after hepaticischemia/reperfusion injury. (2014)
  • Author(s): Ohkubo H, Ito Y, Minamino T, Eshima K, Kojo K, Okizaki S, Hirata M, Shibuya M, Watanabe M, Majima M.
  • Journal Title: PLoS One Volume: 9 Issue: 8 Pages: e105533-e105533
  • DOI: 10.1371/journal.pone.0105533
  • Peer Reviewed / Open Access
• [Journal Article] Prostanoid induces premetastatic niche in regional lymph nodes. (2014)
  • Author(s): Ogawa F, Amano H, Eshima Y, Ito Y, Matsui Y, Hosono K, Kitasato H, Iyoda A, Iwabuchi K, Kumagai Y, Satoh Y, Narumiiya S, Majima M.
  • Journal Title: J. Clin. Invest. Volume: 124 Issue: 11 Pages: 4882-4894
  • DOI: 10.1172/jci73530
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Downregulation of the proangiogenic prostaglandin E receptor EP3 and reduced angiogenesis in a mouse model of diabetes mellitus. (2014)
  • Author(s): Oba K, Hosono K, Amano H, Okizaki S, Ito Y, Shichiri M, Majima M.
  • Journal Title: Biomed Pharmacother. Volume: 68 Issue: 8 Pages: 1125-1133
  • DOI: 10.1016/j.biopha.2014.10.022
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Role of Prostanoids in Regulation of Pathological Lymphangiogenesis (2018)
  • Author(s): Masataka Majima
  • Organizer: Lymphatics Gordon Research Conference
  • Int'l Joint Research / Invited
• [Presentation] An inducible mPGES-1 promotes lung metastasis via SDF-1/CXCR4-mediated recruitment of MDSCs (2017)
  • Author(s): Hideki Amano, Ryo Takahashi, Masataka Majima
  • Organizer: 第９０回日本薬理学会年会（招聘シンポジウム）
  • Place of Presentation: 長崎 ブリックホール
  • Year and Date: 2017-03-15
  • Invited
• [Presentation] Prostaglandins as Regulators of Neovascularization (2017)
  • Author(s): Masataka Majima
  • Organizer: Angiogenesis Gordon Research Conference
  • Int'l Joint Research / Invited
• [Presentation] Roles of RAMP-1 Signalling as a Neuronal Cue of Lymphangiogenesis (2016)
  • Author(s): Masataka Majima
  • Organizer: Gordon Research Conference
  • Place of Presentation: Ventura, CA, USA
  • Year and Date: 2016-03-20
  • Int'l Joint Research / Invited
• [Presentation] Neuronal Cue for Neovascularization; CGRP-RAMP1 Signaling (2015)
  • Author(s): Masataka Majima
  • Organizer: Gordon Research Conference
  • Place of Presentation: Newport, RI, USA
  • Year and Date: 2015-08-02
  • Int'l Joint Research / Invited
• [Presentation] Roles of prostaglandins in regulation of plasticity of lymphatics and lymph nodes (2015)
  • Author(s): Masataka Majima
  • Organizer: 6th International Conference on Phospholipase A2 and Lipid Mediators (Symposium)
  • Place of Presentation: Keio Plaza Hotel、Tokyo
  • Year and Date: 2015-02-10 – 2015-02-12
  • Invited
• [Presentation] Roles of Arachidonic Acid Metabolites in Angiogenesis (2014)
  • Author(s): Masataka Majima
  • Organizer: Gordon Research Conference; Endothelial Cell Phenotypes in Health & Disease
  • Place of Presentation: Girona, Spain
  • Year and Date: 2014-07-06 – 2014-07-11
  • Invited
• [Presentation] Roles of prostanoids in regulation of angiogenesis and lymphagiogenesis (2014)
  • Author(s): Masataka Majima
  • Organizer: Research Forum on Cancer Biology in Moses Cancer Center
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-05-20
  • Invited
• [Book] 未知なるリンパ 炎症とリンパ管新生 (2017)
  • Author(s): 馬嶋正隆
  • Total Pages: 147
  • Publisher: 羊土社
  • ISBN: 9784758101608
• [Book] NEW薬理学第７版 (2017)
  • Author(s): 馬嶋正隆
  • Publisher: 南江堂
• [Book] 標準薬理学第７版、第２３章 免疫炎症系 (2015)
  • Author(s): 馬嶋正隆
  • Total Pages: 50
  • Publisher: 医学書院
• [Book] 標準薬理学第７版 (2015)
  • Author(s): 馬嶋正隆、監修今井正、編集飯野正光
  • Total Pages: 674
  • Publisher: 医学書院
• [Remarks] 北里大学医学部薬理学単位
  • URL: http://www.med.kitasato-u.ac.jp/pharm/
• [Remarks] 北里大学医学部薬理学単位ホームページ
  • URL: http://www.med.kitasato-u.ac.jp/pharm/