Animal model of chronic thromboembolic pulmonary hypertension by cells proliferating within pulmonary arteries

• Project/Area Number: 16K19444
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba University
• Principal Investigator: Takayuki Jujo 千葉大学, 大学院医学研究院, 特任助教 (90736422)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); 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: 肺高血圧症 / 肺塞栓症 / 肺動脈内膜肉腫 / 慢性血栓塞栓性肺高血圧症 / 肺循環 / モデル動物 / 血管内膜肉腫 / 肺血栓塞栓症 / 動物モデル

Outline of Final Research Achievements

Establishing an animal model of chronic thromboembolic pulmonary hypertension (CTEPH) was not successful.We injected intravenously sarcoma-like cells (SCLs cellls), myofibroblast cells to SCID mice or F344 rats. However, those cells did not proliferated. We established a cell line of pulmonary intimal sarcoma during the studying period. The cells have the requirement of malignant cells including tumorgenesis in rats. The cells highly expressed tyrosine kinase receptors (TKRs) including platelete-derived growth factor and vascular endothelial growth factor receptors (PDGFR and VEGFR). Pazopanib, which is a tyrosine kinase inhibitor (TKIs), could inhibit the proliferation of PIS-1 cells and the growth of subcutaneous tumor in rats. It was suggested that TKRs might be an treatment target for pulmonary intimal sarcoma.

Academic Significance and Societal Importance of the Research Achievements

肺動脈内膜肉腫細胞では血小板由来増殖因子受容体(PDGFR)や血管内皮細胞増殖因子受容体(VEGFR)などが高発現し、これらを阻害するチロシンキナーゼ受容体阻害薬であるPazopanibがこの細胞の増殖や腫瘍増大を抑制することを発見した。本来の目的を離れた副次的な産物であるが、本研究の成果はこうした肺動脈原発腫瘍の今後の治療進歩に寄与しうるものであると考える。

Research Products

• [Journal Article] Characterization of pulmonary intimal sarcoma cells isolated from a surgical specimen: In vitro and in vivo study. (2019)
  • Author(s): Sanada TJ, Sakao S, Naito A, Ishibashi-Ueda H, Suga M, Shoji H, Miwa H, Suda R, Iwasawa S, Tada Y, Ishida K, Tanabe N, Tatsumi K
  • Journal Title: PLoS One Volume: 14 Issue: 3 Pages: e0214654-e0214654
  • DOI: 10.1371/journal.pone.0214654
  • Peer Reviewed / Open Access
• [Journal Article] Adult Partial Anomalous Pulmonary Venous Connection With Drainage to Left Atrium and Inferior Vena Cava Clearly Visualized on a Combination of Multiple Imaging Techniques (2017)
  • Author(s): Kasai H, Sugiura T, Arano T, Shoji H, Jujo T, Sakao S, Tanabe N, Tatsumi K.
  • Journal Title: Circulation Journal Volume: 81 Issue: 10 Pages: 1547-1549
  • DOI: 10.1253/circj.CJ-17-0029
  • NAID: 130006099897
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic and pathophysiological marker for patients with chronic thromboembolic pulmonary hypertension: Usefulness of diffusing capacity for carbon monoxide at diagnosis. (2017)
  • Author(s): Suda R, Tanabe N, Ishida K, Kato F, Urushibara T, Sekine A, Nishimura R, Jujo T, Sugiura T, Shigeta A, Sakao S, Tatsumi K.
  • Journal Title: Respirology. Volume: 22(1) Issue: 1 Pages: 179-186
  • DOI: 10.1111/resp.12883
  • Peer Reviewed
• [Journal Article] Severe Pulmonary Arteriopathy Is Associated with Persistent Hypoxemia after Pulmonary Endarterectomy in Chronic Thromboembolic Pulmonary Hypertension. (2016)
  • Author(s): Jujo T, Tanabe N, Sakao S, Ishibashi-Ueda H, Ishida K, Naito A, Kato F, Takeuchi T, Sekine A, Nishimura R, Sugiura T, Shigeta A, Masuda M, Tatsumi K.
  • Journal Title: PLoS One. Volume: 11 Issue: 8 Pages: e0161827-e0161827
  • DOI: 10.1371/journal.pone.0161827
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pulmonary haemodynamics are correlated with intimal lesions in a rat model of severe PAH: attenuation of pulmonary vascular remodelling with ambrisentan. (2016)
  • Author(s): Takeuchi T, Sakao S, Kato F, Naito A, Jujo T, Yasuda T, Tanabe N, Tatsumi K.
  • Journal Title: Histol Histopathol Volume: 31 Pages: 1357-65
  • Peer Reviewed
• [Journal Article] Coagulation-Fibrinolysis System and Postoperative Outcomes of Patients With Chronic Thromboembolic Pulmonary Hypertension (2016)
  • Author(s): Kato F, Tanabe N, Ishida K, Suda R, Sekine A, Nishimura R, Jujo T, Sugiura T, Sakao S, Tatsumi K.
  • Journal Title: Circulation Journal Volume: 80 Issue: 4 Pages: 970-979
  • DOI: 10.1253/circj.CJ-15-1208
  • NAID: 130005139583
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Right ventricular sugars and fats in chronic thromboembolic pulmonary hypertension. (2016)
  • Author(s): Sakao S, Daimon M, Voelkel NF, Miyauchi H, Jujo T, Sugiura T, Ishida K, Tanabe N, Kobayashi Y, Tatsumi K.
  • Journal Title: Int J Cardiol. Volume: 219 Pages: 143-9
  • DOI: 10.1016/j.ijcard.2016.06.010
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 肺動脈内膜肉腫 (pulmonary artery intimal sarcoma)の細胞株樹立 (2017)
  • Author(s): 重城喬行、坂尾誠一郎、植田初江、内藤亮、菅正樹、三輪秀樹、松村茜弥、須田理香、加藤史照、西村倫太郎、石田敬一、増田政久、田邉信宏、巽浩一郎
  • Organizer: 第57回日本呼吸器学会学術講演会
• [Presentation] 症例から考えるCTEPHの診断と治療 (2016)
  • Author(s): 重城喬行
  • Organizer: 第５６回日本呼吸器学会学術講演会
  • Place of Presentation: 国立京都国際会館(京都府京都市)
  • Invited
• [Presentation] 安定期CTEPHに対するWarfarinの血栓予防効果と出血リスクの評価 (2016)
  • Author(s): 重城喬行、田邉信宏、坂尾誠一郎、杉浦寿彦 、須田理香,内藤亮, 三輪秀樹、山本慶子、松村茜弥、佐々木茜、江間亮吾、笠井大、加藤史照、西村倫太郎、関根亜由美、巽浩一郎
  • Organizer: 第１回日本肺高血圧・肺循環学会学術集会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
• [Presentation] 肺血栓塞栓症の病態解明を目指して (2016)
  • Author(s): 重城喬行
  • Organizer: 第53回日本臨床生理学会総会
  • Place of Presentation: シェ―ンバッハ・サボー(東京都千代田区)
• [Presentation] ワルファリンによる抗凝固療法下の慢性血栓塞栓性肺高血圧症患者における出血および血栓症再発リスク (2016)
  • Author(s): 重城喬行、田邉信宏、坂尾誠一郎、杉浦寿彦、関根亜由美、西村倫太郎、須田理香、内藤亮、三輪秀樹、山本慶子、佐々木茜、松村茜弥、江間亮吾、笠井大、加藤史照、巽浩一郎
  • Organizer: 第23回肺塞栓症研究会学術集会
  • Place of Presentation: 秋葉原コンベンションホール(東京都千代田区)