Exploration of mechanisms underlying organ-specific aberrant VEGF signaling in sepsis and development of innovative therapeutic approaches based on microcirculation

• Project/Area Number: 25462812
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: University of Tsukuba
• Principal Investigator: JESMIN Subrina 筑波大学, 体育系, 研究員 (60374261)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 敗血症 / 外科系臨床医学 / 救急医学 / 集中治療学 / 医学

Outline of Final Research Achievements

We found vascular endothelial growth factor (VEGF) is a potential factor for the development of multiple organ dysfunction syndrome (MODS) in sepsis. And VEGF has organ and tissue specific role and function in MODS in sepsis. In the current project, we used various pharmacological interventions for the treatment of MODS from early sepsis, some drugs like endothelin blockade, TNF-alpha blockade, protease activated receptor 2 (PAR2) blockade, VEGF receptor antagonist, ultra-short acting beta blocker as therapeutics for MODS in sepsis.
In this report, we are providing in details how downregulated VEGF in heart tissue in early sepsis can be reversed with the treatment of an ultra-short acting beta blocker, landiolol hydrochloride. Indeed, myocardial dysfunction is a common complication in sepsis which is associated with decreased myocardial level of VEGF. Beta blocker plays crucial role in normalizing the sepsis-mediated decreased cardiac VEGF levels.

Research Products

• [Journal Article] Activated protein C does not increase in the early phase of trauma with disseminated intravascular coagulation: comparison with acute coagulopathy of trauma-shock. (2016)
  • Author(s): S. Jesmin, S. Gando, T. Wada, M. Hayakawa, A. Sawamura
  • Journal Title: Journal Intensive Care Volume: 4(4) Issue: 1 Pages: 1-1
  • DOI: 10.1186/s40560-015-0123-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hyperinflation deteriorates arterial oxygenation and lung injury in a rabbit model of ARDS with repeated open endotracheal suctioning. (2015)
  • Author(s): J. Kamiyama, S. Jesmin, H. Sakuramoto, N. Shimojo, M.M. Islam, K. Hagiya, M. Sugano, M. Oki, T. Unoki, S. Kawano, T. Mizutani
  • Journal Title: BMC Anesthesiology15 Volume: 15(73) Issue: 1 Pages: 1-11
  • DOI: 10.1186/s12871-015-0045-5
  • NAID: 120007130246
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Concomitant Down-Regulation of Et1-Etb System and VEGF Angiogenic Signaling in the Frontal Cortex of Endotoximic Mice: A Heightened Vulnerability to Cerebral Microcirculation in Sepsis. (2015)
  • Author(s): Sonobe, S. Jesmin, N. Shimojo, C.N. Mowa, M.M. Islam, T. Khatun, M. Oki, S. Kawano, T. Mizutani
  • Journal Title: Journal of Vascular Medicine and Surgery Volume: 3(4) Issue: 25-26 Pages: 1-7
  • DOI: 10.1016/j.lfs.2013.12.063
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Severity of delirium in the ICU is associated with short term cognitive impairment: A prospective cohort study. (2015)
  • Author(s): H. Sakuramoto, S. Jesmin, T. Unoki, H. Komatsu, T. Mizutani
  • Journal Title: Intensive & Critical Care Nursing Volume: 31(4) Issue: 4 Pages: 250-257
  • DOI: 10.1016/j.iccn.2015.01.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Landiolol Hydrochloride Normalizes Diminished Levels of Cardiac Vascular Endothelial Growth Factor (VEGF) Signaling System Components in Lipopolysaccharide-Induced Sepsis Independent of Inflammatory Markers. (2015)
  • Author(s): Y. Seki, S. Jesmin, M.M. Islam, Y. Ogura, M. Oki, N. Shimojo, T. Khatun, H. Sakuramoto, S. Kawano, T. Mizutani
  • Journal Title: Journal of Vascular Medicine and Surgery Volume: 3(2) Issue: 02 Pages: 1-9
  • DOI: 10.4172/2329-6925.1000193
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Landiolol Hydrochloride Ameliorates Liver Injury in a Rat Sepsis Model by Down Regulating Hepatic TNF-Α (2015)
  • Author(s): Yasuyo Yoshino, Subrina Jesmin, Majedul Islam, Nobutake Shimojo, Hideaki Sakuramoto, Masami Oki, Tanzila Khatun, Masato Suda, Satoru Kawano, Taro Mizutani
  • Journal Title: Journal of Vascular Medicine & Surgery Volume: 3 Issue: 02 Pages: 194-194
  • DOI: 10.4172/2329-6925.1000194
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual blockade of endothelin action exacerbates up-regulated VEGF angiogenic signaling in the heart of lipopolysaccharide-induced endotoxemic rat model. (2014)
  • Author(s): Oki M, Jesmin S, Islam MM, Mowa CN, Khatun T, Shimojo N, Sakuramoto H, Kamiyama J, Kawano S, Miyauchi T, Mizutani T.
  • Journal Title: Life Sci. Volume: 118 Issue: 2 Pages: 364-369
  • DOI: 10.1016/j.lfs.2014.02.008
  • NAID: 120007130485
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of protease activated receptor (PAR) 2 blocking peptide on endothelin-1 levels in kidney tissues in endotoxemic rat model (2014)
  • Author(s): Jesmin S, Shimojo N, Yamaguchi N, et al
  • Journal Title: Life Sci Volume: 102(2) Issue: 2 Pages: 127-33
  • DOI: 10.1016/j.lfs.2014.03.013
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of circulatory and pulmonary endothelin-1 levelsin a lavage-induced surfactant-depleted lung injury rabbit model with repeated open endotracheal suctioning and hyperinflation. (2014)
  • Author(s): Kamiyama J, Jesmin S, Sakuramoto H, Shimojo N, Islam MM, Khatun T, Oki M, Kawano S, Mizutani T.
  • Journal Title: Life Sciences Volume: S0024-3205(14) Issue: 2 Pages: 401-9
  • DOI: 10.1016/j.lfs.2014.04.001
  • Peer Reviewed / Open Access
• [Journal Article] Significant reversal of cardiac upregulated endothelin-1 system in a rat model of sepsis by landiolol hydrochloride. (2014)
  • Author(s): Seki Y, Jesmin S, Shimojo N, Islam MM, Rahman MA, Khatun T, Sakuramoto H, Oki M, Sonobe A, Kamiyama J, Hagiya K, Kawano S, Mizutani T.
  • Journal Title: Life Sciences Volume: S0024-3205(14) Issue: 2 Pages: 405-6
  • DOI: 10.1016/j.lfs.2014.04.005
  • Peer Reviewed / Open Access
• [Journal Article] Potential amelioration of upregulated renal HIF-1alpha-endothelin-1 system by landiolol hydrochloride in a rat model of endotoxemia. (2014)
  • Author(s): Ogura Y, Jesmin S, Yamaguchi N, Oki M, Shimojo N, Islam MM, Khatun T, Kamiyama J, Sakuramoto H, Hagiya K, Kawano S, Mizutani T.
  • Journal Title: Life Sci. Volume: 118 Issue: 2 Pages: 347-356
  • DOI: 10.1016/j.lfs.2014.05.007
  • NAID: 120007130487
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The role of angiogenic factors and their soluble receptors in acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) associated with critical illness (2013)
  • Author(s): Wada T
  • Journal Title: J Inflamm (Lond) Volume: 10 Issue: 1 Pages: 6-6
  • DOI: 10.1186/1476-9255-10-6
  • Peer Reviewed / Open Access
• [Journal Article] Angiogenic factors and their soluble receptors for predicting organ dysfunction in disseminated intravascular coagulation associated with sepsis. (2013)
  • Author(s): Jesmin S
  • Journal Title: Inflammation Volume: 36 Issue: 1 Pages: 186-196
  • DOI: 10.1007/s10753-012-9534-6
  • Peer Reviewed / Open Access
• [Journal Article] Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: Comparison with acute coagulopathy of trauma-shock (2013)
  • Author(s): Yanagida Y, Gando S, Sawamura A, Hayakawa M, Uegaki S, Kubota N, Homma T, Ono Y, Honma Y, Wada T, Jesmin S
  • Journal Title: Surgery Volume: 154 Issue: 1 Pages: 48-57
  • DOI: 10.1016/j.surg.2013.02.004
  • Peer Reviewed / Open Access
• [Journal Article] Coagulofibrinolytic changes in patients with disseminated intravascular Coagulation associated with post-cardiac arrest syndrome―Fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction. (2013)
  • Author(s): Wada T, 他6名
  • Journal Title: Thrombosis Research Volume: 132 Issue: 1 Pages: e64-e69
  • DOI: 10.1016/j.thromres.2013.05.010
  • Peer Reviewed / Open Access
• [Journal Article] Repeated open endotracheal suctioning causes gradual desaturation but does not exacerbate lung injury compared to closed endotracheal suctioning in a rabbit model of ARDS. (2013)
  • Author(s): Sakuramoto H, Shimojo N, Jesmin S, Unoki T, Kamiyama J, Oki M, Miya K, Kawano S, Mizutani T.
  • Journal Title: BMC Anesthesiology Volume: 13(1) Issue: 1 Pages: 47-47
  • DOI: 10.1186/1471-2253-13-47
  • NAID: 120007130567
  • Peer Reviewed
• [Presentation] Three hours treatment of landiolol hydrochloride, an ultra-short-acting β-blocker, is not effective to reverse altered pulmonary endothelin-1 system in acute lung injury in a rat model of early hours of endotoxemia (2015)
  • Author(s): Yujiro Matsuishi, Subrina Jesmin, Sakuramoto hideaki, Nobutake Shimojo, Shila Akhtar, Sohel Zaedi, Tanzila Khatun, Satoru Kawano, Taro Mizutani
  • Organizer: The Fourteenth International Conference on Endothelin
  • Place of Presentation: Savannah, GA, United States of America
  • Year and Date: 2015-09-02
  • Int'l Joint Research
• [Presentation] Amelioration of acute liver injury with the blockade of protease activated receptor-2 (PAR2) through the suppression of upregulated levels of Endothelin-1 and TNF-α in a rat model of endotoxemia (2015)
  • Author(s): Subrina Jesmin, Sohel Zaedi, Nobutake Shimojo, Shila Akhtar, Md. Arifur Rahman, Yujiro Matsuishi, Naoto Yamaguchi, Sayeeda Nusrat Sultana, Satoshi Gando, Satoshi Sakai, Saturo Kawano, Takashi Miyauchi
  • Organizer: The Fourteenth International Conference on Endothelin
  • Place of Presentation: Savannah, GA, United States of America
  • Year and Date: 2015-09-02
  • Int'l Joint Research
• [Presentation] ＬＰSＳ誘発性敗血症性腎障害へのβ1遮断薬の影響―腎組織の炎症系とEndothelin系からの考察― (2014)
  • Author(s): 1.山口直人, Jesmin S, 小倉吉保, 下條信威, 山木万里郎, 鹿野直人, 大瀬寛高, 水谷太郎.
  • Organizer: 第５６回茨城腎研究会
  • Place of Presentation: 茨城
  • Year and Date: 2014-06-17
• [Presentation] LPS誘発性敗血症ラットモデルに於ける臓器特異的VEGF発現 (2014)
  • Author(s): Jesmin S, Sonobe A, Wada T, Shimojo N, Gando S, Kawano S, Mizutani T
  • Organizer: 第41回日本集中治療医学会
  • Place of Presentation: 京都市
• [Presentation] 敗血症マウス前頭葉における炎症性サイトカイン発現の経時的変化の解析 (2014)
  • Author(s): Sonobe A, Jesmin S, Shimojo N, Kawano S, Mizutani T
  • Organizer: 第41回日本集中治療医学会
  • Place of Presentation: 京都市
• [Presentation] エンドセリン両受容体遮断薬は敗血症モデルラットの活性化したVEGF血管新生シグナルを増強する (2014)
  • Author(s): Ooki S, Jesmin S, Shimojo N, Hagiya K, Yamasaki Y, Kawano S, Mizutani T
  • Organizer: 第41回日本集中治療医学会
  • Place of Presentation: 京都市
• [Presentation] ショックの全身管理に伴う凝固薬の併用と使用基準の検討. (2014)
  • Author(s): Miya K, Shimojo N, Hagiya K, Sakuramoto H, Unoki K, Jesmin S, Kawano S, Mizutani T
  • Organizer: 第41回日本集中治療医学会
  • Place of Presentation: 京都市
• [Presentation] The Dynamics of Angiogenic Factors and Their Soluble Receptors in Relation to Organ Dysfunction in Disseminated Intravascular Coagulation Associated with Sepsis. (2013)
  • Author(s): Jesmin S, Shimojo N, Wada T, Kawano S, Gando S, Mizutani T
  • Organizer: 第22回日本集中治療医学会関東甲信越地方会
  • Place of Presentation: 茨城県つくば市
• [Presentation] ole of angiogenic growth factors in post cardiac arrest syndrome. (2013)
  • Author(s): Shimojo N, Jesmin S, Wada T, Kawano S, Gando S, Mizutani T
  • Organizer: 第22回日本集中治療医学会関東甲信越地方会
  • Place of Presentation: 茨城県つくば市
• [Presentation] Effects of landiolol hydrochloride, an ultra-short-acting β-blocker, on cardiac endothelin system in a rat model of endotoxemia: a possible relevance with cardiac functional compensatory events at the early phase of sepsis (2013)
  • Author(s): Seki Y, Jesmin S, Shimojo N, Islam M, Khatun T, Sakuramoto H, Kamiyama J, Hagiya K, Kawano S, Mizutani T
  • Organizer: The Thirteenth International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Dual endothelin blockade exacerbates upregulated VEGF angiogenic signaling in the heart of lipopolysaccharide -induced endotoxemic rat model (2013)
  • Author(s): Oki M, Jesmin S, Shimojo N, Islam M, Khatun T,Kawano S, Mizutani T
  • Organizer: The Thirteenth International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Upregulated pulmonary endothelin-1 in acute lung injury is not normalized through landiolol hydrochloride treatment, an ultra-short-acting β-blocker, in a rat model of endotoxemia (2013)
  • Author(s): Shimojo N, Jesmin S, Seki Y, Sakuramoto H, Islam M, Khatun T, Kawano S, Mizutani T
  • Organizer: The Thirteenth International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Effects of repeated closed vs. open endotracheal suctioning during mechanical ventilation on the pulmonary and circulatory levels of endothelin-1 in a lavage induced surfactant depleted rabbit ARDS model (2013)
  • Author(s): Sakuramoto H, Jesmin S, Shimojo N, Kamiyama J, Islam M, Khatun T, Kawano S, Mizutani T
  • Organizer: The Thirteenth International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Blood pressure independent downregulation of plasma endothelin-1 levels in a lavage-induced surfactant depleted rabbit ARDS model: Effects of various respiratory maneuvers on endothelin-1 levels (2013)
  • Author(s): Kamiyama J, Jesmin S, Sakuramoto H, Islam M, Khatun T, Shimojo N, Kawano S, Mizutani T
  • Organizer: The Thirteenth International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Potential amelioration of upregulated renal HIF1alpha-Endothelin 1 system through landiolol hydrochloride in a rat model of endotoxemia: a possible linkage to the increased renal vascular resistance based on renal microcirculation alteration in sepsis (2013)
  • Author(s): Ogura Y, Shimojo N, Jesmin S, Seki Y, Sakuramoto H, Hagiya K, Kawano S, Mizutani T
  • Organizer: The Thirteenth International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Concomitant downregulation of ET-1-ETB system and VEGF angiogenic signaling in the frontal cortex of a murine model of endotoxemia: A double threat to cerebral microcirculation in sepsis (2013)
  • Author(s): 7. Sonobe A, Jesmin S, Shimojo N, Islam M, Khatun T, Oki M, Kawano S, Mizutani T
  • Organizer: The Thirteenth International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Organ specific differential effect of landiolol hydrochloride, an ultra-short-acting β-blocker, on endothelin system in an animal model of sepsis: A new horizon of exploring the therapeutic potential of target molecule based drug innovation in sepsis
  • Author(s): Jesmin S
  • Organizer: Annual Research Meeting Sponsored by Ono Pharmaceuticals
  • Place of Presentation: 茨城県つくば市
  • Invited