Lymphangiogenesis as a regulator of fluid homeostasis in pathological settings

• Project/Area Number: 24659119
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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): KITASATO Hidero 北里大学, 医療衛生学部, 教授 (90195256)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: プロスタノイド / リンパ管新生 / ホメオスタシス / 体液 / 高血圧 / 炎症 / LPS / COX-2 / 腹水 / アラキドン酸代謝物 / COX / PGE合成酵素 / 皮下組織 / ナトリウム / Lyve-1 / VEGF-C / 食塩

Outline of Final Research Achievements

We had tested the roles of an inducible prostaglandin E synthase, mPGES-1 in facilitation of inflammation-induced lymphangiogenesis (IL) elicited by lipopollysccharide (LPS). With LPS i.p. injections, lymphatics in diaphragm were widened and Lyve-1-positive ladder-structured lymphatics were increased temporally in comparison with vehicle-treated wild type mice (WT). This increase of lymphangiogenesis was accompanied with increased expressions of vascular endothelial growth factor (VEGF)-C/D. In mPGES-1 knockout mice (KO), IL was suppressed with reduced expressions of VEGF-C/D. When FITC-dextran was injected into peritoneal cavities, the residual amount of FITC-dextran was reduced significantly in WT with LPS treatment. This reduction was significantly restored in mPGES-1 KO. These results suggested that mPGES-1 had significant roles in facilitation of lymphangiogenesis active in fluid drainage during IL, and that this enzyme will be a novel target for controlling IL.

Research Products

• [Journal Article] Prostanoid induces premetastatic niche in regional lymph nodes mediated by chemokine system in dendritic cells. (2015)
  • Author(s): Ogawa F, Amano H, Eshima K, Ito Y et al
  • Journal Title: J Clin Invest. Volume: 124 Pages: 4882-4894
  • DOI: 10.1172/jci73530
  • 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] 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] The role of vascular endothelial growth factor receptor-1 signaling in compensatory contralateral lung growth following unilateral pneumonectomy. (2015)
  • Author(s): Matsui Y, Amano H, Ito Y, Eshima K, Tamaki H, Ogawa F, Iyoda A, Shibuya M, Kumagai Y, Satoh Y, Majima M.
  • Journal Title: Laboratory Investigation. Volume: 未定 Pages: 1-10
  • 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
  • DOI: 10.1371/journal.pone.0105533
  • Peer Reviewed / Open Access
• [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 Pages: 1125-1133
  • DOI: 10.1016/j.biopha.2014.10.022
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vascular endothelial growth factor receptor 1 signaling facilitates gastric ulcer healing and angiogenesis through the up regulation of epidermal growth factor expression on VEGFR1+ CXCR4+ cells recruited from bone marrow. (2014)
  • Author(s): Sato T., Amano H., Ito Y., Eshima K., Minamino T., Ae T., Katada C., Ohno T., Hosono K., Suzuki T., Shibuya M., Koizumi W., Majima M.
  • Journal Title: J Gastroenterol Volume: 49 Pages: 455-469
  • DOI: 10.1007/s00535-013-0869-z
  • Peer Reviewed
• [Journal Article] Roles of microsomal prostaglandin E synthase-1 in lung metastasis formation in prostate cancer RM9 cells. (2014)
  • Author(s): Takahashi R., Amano H., Satoh T., Tabata K., Ikeda M., Kitasato H., Akira S., Iwamura M., Majima M.
  • Journal Title: Biomedicine & Pharmacotherapy Volume: 68 Pages: 71-77
  • DOI: 10.1016/j.biopha.2013.10.008
  • Peer Reviewed
• [Journal Article] Roles of receptor activity-modifying protein 1 in angiogenesis and lymphangiogenesis during skin wound healing in mice. (2014)
  • Author(s): Takahashi R., Amano H., Satoh T., Tabata K., Ikeda M., Kitasato H., Akira S., Iwamura M., Majima M.
  • Journal Title: FASEB J. Volume: 28 Pages: 1237-1247
  • DOI: 10.1096/fj.13-238998
  • Peer Reviewed
• [Journal Article] NSAID, aspirin delays gastric ulcer healing with reduced accumulation of CXCR4^+VEGFR1^+ cells to the ulcer granulation tissues (2014)
  • Author(s): Ogawa F., Amano H., Ito H., Matsui Y., Hosono K., Kitasato H., Satoh Y., Majima M.
  • Journal Title: Biomed Pharmaco Volume: 68 Pages: 607-613
  • DOI: 10.1016/j.biopha.2013.11.006
  • Peer Reviewed
• [Journal Article] Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment. (2013)
  • Author(s): Ohkubo H., Ito Y., Minamino T., Mishima T., Hirata M., Hosono K., Shibuya M., Yokomizo T., Shimizu T., Watanabe M., Majima M.
  • Journal Title: FASEB J Volume: 27 Pages: 3132-3143
  • DOI: 10.1096/fj.13-227421
  • Peer Reviewed
• [Journal Article] Angiotensin II Type 1A Receptor Signaling Facilitates Tumor Metastasis Formation through P-selectin-mediated Interaction of Tumor Cells with Platelets and Endothelial Cells (2013)
  • Author(s): Amano H, Ito Y, Ogawa F, Eshima K, Suzuki T, Oba K, Matsui Y, Kato S, Fukui T, Nakamura M, Kitasato H, Fukamizu A, Majima M
  • Journal Title: American journal of Pathology Volume: 182(2) Pages: 553-564
  • DOI: 10.1016/j.ajpath.2012.10.026
  • Peer Reviewed
• [Journal Article] Tumor apoptosis in prostate cancer by PGD(2) and its metabolite 15d-PGJ(2) in murine model (2013)
  • Author(s): Nakamura M, Tsumura H, Satoh T, Matsumoto K, Maruyama H, Majima M, Kitasato H.
  • Journal Title: Biomed Pharmacother Volume: 67 Pages: 66-71
  • DOI: 10.1016/j.biopha.2012.10.012
  • Peer Reviewed
• [Journal Article] In vivo kinetics of indoxyl sulfate in humans and its renal interaction with angiotensin-converting enzyme inhibitor quinapril in rats (2012)
  • Author(s): Fujita T, Ishihara K, Yasuda S, Nakamura T, Maeda M, Kobayashi M, Sahashi K, Ikeda Y, Kumagai Y, Majima M.
  • Journal Title: J Pharmacol Exp Ther Volume: 341 Pages: 626-33
  • DOI: 10.1124/jpet.111.187732
  • Peer Reviewed
• [Journal Article] Thromboxane A(2) receptor signaling facilitates tumor colonization through P-selectin-mediated interaction of tumor cells with platelets and endothelial cells (2012)
  • Author(s): Matsui Y, Amano H, Ito Y, Eshima K, Suzuki T, Ogawa F, Iyoda A, Satoh Y, Kato S, Nakamura M, Kitasato H, Narumiya S, Majima M
  • Journal Title: Cancer Science Volume: 103(4) Pages: 33-38
  • DOI: 10.1111/j.1349-7006.2012.02200.x
  • Peer Reviewed
• [Journal Article] Thromboxane A#8322; receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment. (2012)
  • Author(s): Minamino T, Ito Y, Ohkubo H, Hosono K, Suzuki T, Sato T, Ae T, Shibuya A, Sakagami H, Narumiya S, Koizumi W, Majima M
  • Journal Title: Toxicology and Applied Pharmacology Volume: 259(1) Pages: 104-114
  • DOI: 10.1016/j.taap.2011.12.013
  • Peer Reviewed
• [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 (Shinjuku,Tokyo)
  • Year and Date: 2015-02-10 – 2015-02-12
  • Invited
• [Presentation] Prostanoids as Regulators of Pathological Lymphangiogenesis (2014)
  • Author(s): Majima M., Hosono K., Amano H., Ogawa F., Park K.
  • Organizer: GRC Molecular Mechanisms in Lymphatic Function & Disease
  • Place of Presentation: Barga (Italy)
  • 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: 2014-05-12
  • Invited
• [Presentation] 病態時のリンパ管新生とリンパ流を制御するプロスタグランジンの役割 (2013)
  • Author(s): 馬嶋正隆
  • Organizer: 第３７回日本リンパ学会総会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] Roles of Prostanoids in Pathological Lymphangiogenesis (2013)
  • Author(s): 馬嶋正隆
  • Organizer: 第3回リンパ学に関する松本カンファランス
  • Place of Presentation: 松本
  • Invited
• [Presentation] Prostanoids regulate tumor stromal profiles via specific G-protein coupled receptors (2013)
  • Author(s): Majima M., Hosono K., Suzuki T., Amano H., Kato H., Ogawa F., Park K.
  • Organizer: 4th International conference on tumor-host interaction and Angiogenesis
  • Place of Presentation: Ascona (Switzerland)
  • Invited
• [Presentation] Microsomal prostaglandin E synthase-1 as a regulator of angiogenesis (2013)
  • Author(s): Majima M., Hosono K., Suzuki T., Amano H.
  • Organizer: GRC Angiogenesis
  • Place of Presentation: New Port (United States)
  • Invited
• [Presentation] Roles of prostaglandins in enhancement of angiogenesis and lymphangiogenesis during the developments of cancers and inflammation. (2012)
  • Author(s): Majima M.
  • Organizer: Keystone Symposium: Inflammation during Carcinogenesis
  • Place of Presentation: Dublin (アイルランド)
  • Invited
• [Presentation] Roles of thromboxane receptor signaling in enhancement of angiogenesis. (2012)
  • Author(s): Majima M.
  • Organizer: 17th International Vascular Biology Meeting (IVBM) 2012
  • Place of Presentation: Wiesbaden（ドイツ）
  • Invited
• [Presentation] 病態時の脈管新生を制御する脂質メディエーターの役割 (2012)
  • Author(s): 馬嶋正隆
  • Organizer: 千里ライフサイエンスセミナー D5 脂質メディエーターと疾患
  • Place of Presentation: 大阪
  • Invited
• [Presentation] ショック研究における基礎医学と臨床医学の連携 (2012)
  • Author(s): 馬嶋正隆
  • Organizer: 第２７回日本Shock学会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Roles of prostaglandins in enhancement of angiogenesis and lymphangiogenesis in diseases. (2012)
  • Author(s): Majima M.
  • Organizer: 1st International Symposium on Lipid Mediators
  • Place of Presentation: 福岡
  • Invited
• [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
• [Book] 遺伝子医学MOOK 24号 最新生理活性脂質研究-実験手法、基礎的知識とその応用- (2013)
  • Author(s): 馬嶋正隆、青木淳賢、杉本幸彦、村上誠、横溝岳彦（監修） 他
  • Total Pages: 312
  • Publisher: メディカル ドゥ社
• [Book] 「最新生理活性脂質研究-実験手法、基礎的知識とその応用-」遺伝子医学MOOK 24号 (2013)
  • Author(s): 馬嶋正隆
  • Publisher: メディカル ドゥ社
• [Book] 医学書院 (2013)
  • Author(s): 馬嶋正隆
  • Publisher: 標準薬理学 第７版
• [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/
• [Remarks] 北里大学医学部薬理学・大学院医療系研究科分子薬理学
  • URL: http://www.med.kitasato-u.ac.jp/pharm/