Elucidation of various pathophysiology of refractory pulmonary arterial lesions in PAH rat model with lung transplantation

• Project/Area Number: 15K09210
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba University
• Principal Investigator: Sakao Seiichiro 千葉大学, 医学部附属病院, 講師 (80431740)
• Co-Investigator(Kenkyū-buntansha): 巽 浩一郎 千葉大学, 大学院医学研究院, 教授 (10207061) ; 江本 憲昭 神戸薬科大学, 薬学部, 教授 (30294218) ; 岩田 剛和 千葉県がんセンター(研究所), 呼吸器外科, 部長 (30586681) ; 田邉 信宏 千葉大学, 大学院医学研究院, 特任教授 (40292700) ; 鈴木 秀海 千葉大学, 大学院医学研究院, 講師 (60422226)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肺動脈性肺高血圧症 / 肺移植 / 肺高血圧症 / ラット肺高血圧症モデル / 肺動脈リモデリング

Outline of Final Research Achievements

Refractory pulmonary arterial lesions against vasodilator drugs were confirmed in PAH rat model ( i.e., Su/Hx model). After a successful single lung transplant in normal rats, we tried a single lung transplant in Su/Hx model. However, almost transplants failed due to high pulmonary arterial pressure and right heart overload. In a very few successful cases, pulmonary lesions ameliorated. Subsequently, there was no successful lung transplant n Su/Hx model. Now, together with it, a single lung transplant between male and female rats was tried to elucidate pathophysiology of vascular lesions. Data about bone marrow derived cells in medial and intimal lesions are accumulated by using FISH analysis.

Research Products

• [Journal Article] Long-Term Outcome of Chronic Thromboembolic Pulmonary Hypertension at a Single Japanese Pulmonary Endarterectomy Center (2018)
  • Author(s): Miwa Hideki、Tanabe Nobuhiro、Jujo Takayuki、Kato Fumiaki、Anazawa Rie、Yamamoto Keiko、Naito Akira、Kasai Hajime、Nishimura Rintaro、Suda Rika、Sugiura Toshihiko、Sakao Seiichiro、Ishida Keiichi、Masuda Masahisa、Tatsumi Koichiro
  • Journal Title: Circulation Journal Volume: 82 Issue: 5 Pages: 1428-1436
  • DOI: 10.1253/circj.CJ-17-1242
  • NAID: 130006725978
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endothelial cell-related autophagic pathways in Sugen/hypoxia-exposed pulmonary arterial hypertensive rats. (2017)
  • Author(s): Kato F, Sakao S, Takeuchi T, Suzuki T, Nishimura R, Yasuda T, Tanabe N, Tatsumi K.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 313(5) Issue: 5 Pages: 899-915
  • DOI: 10.1152/ajplung.00527.2016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mosaic attenuation pattern in non-contrast computed tomography for the assessment of pulmonary perfusion in chronic thromboembolic pulmonary hypertension (2017)
  • Author(s): Kasai Hajime、Tanabe Nobuhiro、Fujimoto Kazushi、Hoshi Hiromasa、Naito Jun、Suzuki Ryuto、Matsumura Akane、Sugiura Toshihiko、Sakao Seiichiro、Tatsumi Koichiro
  • Journal Title: Respiratory Investigation Volume: 55 Issue: 5 Pages: 300-307
  • DOI: 10.1016/j.resinv.2017.07.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The dilatation of main pulmonary artery and right ventricle observed by enhanced chest computed tomography predict poor outcome in inoperable chronic thromboembolic pulmonary hypertension. (2017)
  • Author(s): Ema R, Sugiura T, Kawata N, Tanabe N, Kasai H, Nishimura R, Jujo T, Shigeta A, Sakao S, Tatsumi K.
  • Journal Title: Eur J Radiol. Volume: 94 Pages: 70-77
  • DOI: 10.1016/j.ejrad.2017.06.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The anticoagulant effects of warfarin and the bleeding risk associated with its use in patients with chronic thromboembolic pulmonary hypertension at a specialist center in Japan: a retrospective cohort study. (2017)
  • Author(s): Jujo-Sanada T, Tanabe N, Sakao S, Sugiura T, Sekine A, Nishimura R, Suda R, Naito A, Miwa H, Yamamoto K, Sasaki A, Matsumura A, Ema R, Kasai H, Kato F, Tatsumi K.
  • Journal Title: Pulm Circ. Volume: 7(3) Issue: 3 Pages: 684-691
  • DOI: 10.1177/2045893217717258
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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
• [Journal Article] Prominin-1/CD133 expression as potential tissue-resident vascular endothelial progenitor cells in the pulmonary circulation. (2016)
  • Author(s): Sekine A, Nishiwaki T, Nishimura R, Kawasaki T, Urushibara T, Suda R, Suzuki T, Takayanagi S, Terada J, Sakao S, Tada Y, Iwama A, Tatsumi K.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 310 Issue: 11 Pages: 1357-65
  • DOI: 10.1152/ajplung.00375.2014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Takeuchi T,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: 1259-64
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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] Synergistic Effects of ACE Insertion/Deletion and GNB3 C825T Polymorphisms on the Efficacy of PDE-5 Inhibitor in Patients with Pulmonary Hypertension. (2016)
  • Author(s): Nishimura R, Tanabe N, Sekine A, Kasai H, Suda R, Kato F, Jujo T, Sugiura T, Shigeta A, Sakao S, Tatsumi K.
  • Journal Title: Respiration Volume: 91 Issue: 2 Pages: 132-149
  • DOI: 10.1159/000443772
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Importance of carefully interpreting computed tomography images to detect partial anomalous pulmonary venous return. (2016)
  • Author(s): Jujo T, Tanabe N, Sugiura T, Naito A, Shigeta A, Kitazono-Saitoh M, Sakao S, Tatsumi K.
  • Journal Title: Respir Investig. Volume: 54 Issue: 1 Pages: 69-74
  • DOI: 10.1016/j.resinv.2015.08.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pulmonary haemodynamics are correlated with intimal lesions in a rat model of severe PAH: attenuation of pulmonary vascular remodelling with ambrisentan (2015)
  • Author(s): Takao Takeuchi; Seiichiro Sakao; Fumiaki Kato; Akira Naito; Takayuki Jujo; Tadashi Yasuda; Nobuhiro Tanabe; Koichiro Tatsum
  • Journal Title: HISTOLOGY AND HISTOPATHOLOGY Volume: N/A
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Increased Right Ventricular Fatty Acid Accumulation in Chronic Thromboembolic Pulmonary Hypertension. (2015)
  • Author(s): Sakao S, Miyauchi H, Voelkel NF, Sugiura T, Tanabe N, Kobayashi Y, Tatsumi K.
  • Journal Title: Ann Am Thorac Soc. Volume: 12 Issue: 10 Pages: 1465-72
  • DOI: 10.1513/annalsats.201504-236le
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Evaluation of the Microcirculation in Chronic Thromboembolic Pulmonary Hypertension Patients: The Impact of Pulmonary Arterial Remodeling on Postoperative and Follow-Up Pulmonary Arterial Pressure and Vascular Resistance. (2015)
  • Author(s): Jujo T, Sakao S, Ishibashi-Ueda H, Ishida K, Naito A, Sugiura T, Shigeta A, Tanabe N, Masuda M, Tatsumi K.
  • Journal Title: PLoS One. Volume: 10 Issue: 8 Pages: e0133167-e0133167
  • DOI: 10.1371/journal.pone.0133167
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Determinants of an elevated pulmonary arterial pressure in patients with pulmonary arterial hypertension. (2015)
  • Author(s): Sakao S, Voelkel NF, Tanabe N, Tatsumi K.
  • Journal Title: Respir Res. Volume: 16 Issue: 1 Pages: 84-84
  • DOI: 10.1186/s12931-015-0246-y
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Vascular Repair by Tissue-Resident Endothelial Progenitor Cells in Endotoxin-Induced Lung Injury. (2015)
  • Author(s): Kawasaki T, Nishiwaki T, Sekine A, Nishimura R, Suda R, Urushibara T, Suzuki T, Takayanagi S, Terada J, Sakao S, Tatsumi K.
  • Journal Title: Am J Respir Cell Mol Biol. Volume: 53 Issue: 4 Pages: 500-12
  • DOI: 10.1165/rcmb.2014-0185oc
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hypoxia-induced proliferation of tissue-resident endothelial progenitor cells in the lung. (2014)
  • Author(s): Nishimura R, Kawasaki T, Sekine A, Suda R, Urushibara T, Suzuki T, Takayanagi S, Terada J, Sakao S, Tatsumi K
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 15 Issue: 8 Pages: 746-758
  • DOI: 10.1152/ajplung.00243.2014
  • Peer Reviewed / Open Access
• [Presentation] 2017年度日本呼吸器学会学術講演会 熊谷賞受賞講演：細胞機能障害と肺高血圧症：病態機序の解明と新規治療法の開発を目指して. (2017)
  • Author(s): 坂尾誠一郎
  • Organizer: 第57回日本呼吸器学会学術講演会
  • Invited
• [Presentation] ランチョンセミナー（LS24）：APTE or CTEPH? －呼吸器科医が診る肺血栓塞栓症のの診断プロセスについて. (2017)
  • Author(s): 坂尾誠一郎
  • Organizer: 第57回日本呼吸器学会学術講演会
  • Invited
• [Presentation] シンポジウム（S2-4）：肺高血圧症における右室心筋細胞のミトコンドリア機能異常. (2017)
  • Author(s): 坂尾誠一郎
  • Organizer: 第2回日本肺高血圧・肺循環学会学術集会
  • Invited
• [Presentation] パネルディスカッション(PD1-5)：肺高血圧症のゲノム解析：その先へ. (2017)
  • Author(s): 坂尾誠一郎
  • Organizer: 第2回日本肺高血圧・肺循環学会学術集会
  • Invited
• [Presentation] Molecular basis for remodeled pulmonary vasculature and hypertrophied right ventricle in pulmonary hypertension. (2016)
  • Author(s): Sakao S.
  • Organizer: The 122th Conference of Korean academic tuberculosis and respiratory disease (KATRD) Invited lecture
  • Place of Presentation: 韓国 ソウル
  • Year and Date: 2016-11-17
  • Int'l Joint Research / Invited
• [Presentation] シンポジウムS1-2:肺高血圧症患者における右室心筋細胞の代謝機能変化. (2016)
  • Author(s): 坂尾誠一郎
  • Organizer: 53回日本臨床生理学会総会
  • Place of Presentation: シェーンバッハ・サボー（東京都・千代田区）
  • Year and Date: 2016-10-28
  • Invited
• [Presentation] ワークショップ2：肺高血圧症患者における右室心筋細胞の代謝機能変化. (2016)
  • Author(s): 坂尾誠一郎
  • 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）
  • Year and Date: 2016-10-01
  • Invited
• [Presentation] 2016年度日本肺高血圧・肺循環学会学術集会 八巻賞受賞講演：細胞機能障害からみた肺高血圧症の病態機序解明および新規治療法の開発. (2016)
  • Author(s): 坂尾誠一郎
  • 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）
  • Year and Date: 2016-10-01
  • Invited
• [Presentation] Right ventricular sugar and fat in chronic thromboembolic pulmonary hypertension. (2016)
  • Author(s): 2.Sakao S, Daimon M, Voelkel N, Miyauchi H, Jujo T, Sugiura T, Tanabe N, Kobayashi Y, Tatsumi K.
  • Organizer: ATS 2016 International Concerence
  • Place of Presentation: アメリカ サンフランシスコ
  • Year and Date: 2016-05-14
  • Int'l Joint Research
• [Presentation] 教育講演：肺静脈閉塞症／肺毛細血管腫症（PVOD/PCH）. (2016)
  • Author(s): 坂尾誠一郎
  • 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）
  • Year and Date: 2016-04-08
  • Invited
• [Presentation] 学術講演会演題賞（学術部会賞）選考講演会：CTEPH患者における右室脂肪酸取り込みと肺循環動態の評価. (2016)
  • Author(s): 坂尾誠一郎
  • 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）
  • Year and Date: 2016-04-08
  • Invited
• [Presentation] 123I-BMIPP fatty acid analogue imaging as a novel procedure to detect a metabolic disorder of right ventricle cardiocytes in patients with chronic thromboembolic pulmonary hypertension. (2015)
  • Author(s): Sakao S
  • Organizer: ATS 2015 International Concerence Mini-Symposium
  • Place of Presentation: Denver, USA
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] Phenotypically altered and dysfunctional endothelial cells in pulmonary arterial hypertension. (2015)
  • Author(s): Sakao S, Tanabe N, Voelkel N, Tatsumi K.
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2015-04-24
  • Invited
• [Book] sGC刺激薬リオシグアトによる肺高血圧症治療 (2017)
  • Author(s): 坂尾誠一郎 福田恵一 巽浩一郎
  • Total Pages: 119
  • Publisher: メディカルレビュー社
• [Book] Lung Stem Cells in the Epithelium and Vasculature (2015)
  • Author(s): Felty Q, Sakao S, Voelkel NF
  • Publisher: Humana Press, Springer International Publishing Switzerland