Research of sphingosine kinase modification in acute lung injury

• Project/Area Number: 18590848
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kobe University
• Principal Investigator: NISHIMURA Yoshihiro Kobe University, Graduate School of Medicine, Associate Professor (20291453)
• Co-Investigator(Kenkyū-buntansha): KOTANI Yoshikazu Kobe University, Hospital, Assistant Professor (90403287) ; OKADA Taro Kobe University, Graduate School of Medicine, Associate Professor (80304088) ; NISHIUMA Teruaki Kobe University, Graduate School of Medicine, Visiting Medical Scientist (10379414) ; HIRATA Kenichi Kobe University, Graduate School of Medicine, Professor (20283880)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: sphingosine 1-phosphate / sphingosine kinase / lung fibroblast / bronchial asthma

Research Abstract

The metabolism of sphingosine kinase (SPHK)/sphingosine 1-phosphate (SIP) system in lung diseases has been reported recently. In this project, we focused on the role of SPHK in lung epithelial cells and fibroblasts in injured lungs.
1. We investigated the mechanism of myofibroblast differentiation in lung fibroblasts of acute lung injury. Bleomycin treatment increased SPHK expression and fibrotic changes in injured lungs. Our study reported that TGF-beta treatment increased SPHK1 activation in lung fibroblasts. S1P produced by SPHK1 induced the transactivation of S1P receptors and recruitment of activated RhoA. This data was accepted in Am J Respir Cell Mol Biol in 2007.
2. Using mouse asthmatic model, we examined whether the effect of SPHK inhibitors attenuates airway inflammation. The inhalation of SPHK inhibitors by nebulizing maneuver showed significant decrease of airway hyperresponsiveness and eosinophilic inflammation induced by ovalbumin treatment, whereas intravenous delivery showed limited effects. Our data indicated that intratracheal treatment of SPHK inhibitor may be one of therapeutic approach for lung inflammation. This data was accepted in Am J Physiol Lung Cell Mol Physiol in 2008.
3. In this animal model, we found that SPHK activity was increased in bronchial epithelial areas in asthmatic lungs. Then we examined the function of SPHK in goblet cell formation around epithelial walls. In vitro studies using airway liquid interface demonstrated that SPHK was activated and played a pivotal role in cell changes by IL-13 treatment. This data will be exhibited in American Thoracic Society in 2008. Thus, our studies clarified that SPHK works for morphological cell changes in lung inflammation.

Research Products

• [Journal Article] Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model. (2008)
  • Author(s): Nishiuma T, Nishimura Y, Okada T, Kuramoto E, Kotani Y, Jahangeer S, Nakamura S
  • Journal Title: Am J Physiol Lung Cell Mol Physiol (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model (2008)
  • Author(s): Nishiuma, T, Nishimura, Y, Okada, T, Kuramoto, E, Kotani, Y, Jahangeer, S, Nakamura, S
  • Journal Title: Am J Physiol Lung Cell Mol Physiol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1 (2007)
  • Author(s): Kono Y, Nishiuma T, Nishimura Y, Kotani Y, Okada T, Nakamura S, Yokoyama M.
  • Journal Title: Am J Respir Cell Mol Biol 37 Pages: 395-404
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1 (2007)
  • Author(s): Kono, Y, Nishiuma, T, Nishimura, Y, Kotani, Y, Okada, T, Nakamura, S, Yokoyama, M
  • Journal Title: Am J Respir Cell Mol Biol 37 Pages: 395-404
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] スフィンゴリン脂質と呼吸器疾患 (2006)
  • Author(s): 西馬照明、西村善博
  • Journal Title: 喘息 19 Pages: 72-76
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Effect of Sphingosine Kinase on IL-13 Induced Goblet cell Metaplasia (2007)
  • Author(s): Kono Y, Nishiuma T, Kuramoto E, Yamamoto M, Sakashita A, Kobayashi K, Funada Y, Kotani Y, Nishimura Y
  • Organizer: アジア太平洋呼吸器学会(Asian Pacific Society of Respirology)
  • Place of Presentation: Gold Coast, Australia
  • Year and Date: 2007-12-04
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Effect of sphingosine kinase on IL-13 induced goblet cell metaplasia (2007)
  • Author(s): Kono, Y, Nishiuma, T, Nishimura, Y, Okada, T, Kobayashi, K, Funada, Y, Kotani, Y, Nakamura, S, Yokoyama, M
  • Organizer: Asian Pacific Society of Respirology
  • Place of Presentation: Gold Coast, Australia
  • Year and Date: 2007-12-04
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Effect of Sphingosine Kinase on 11-13 Induced Goblet Cell Metaplasia (2007)
  • Author(s): Kono Y, 他8名
  • Organizer: アジア太平洋呼吸器学会(Asian Pacific Society of Respirology)
  • Place of Presentation: Gold Coast, Australia
  • Year and Date: 2007-12-04
• [Presentation] Inhaled treatment of sphingosine kinase inhibition attenuates airway inflammation in ovalbumin(OVA)challenged mice model (2007)
  • Author(s): Nishiuma T, Nishimura Y, Kobayashi K, Kotani Y, Yokoyama M
  • Organizer: 米国胸部疾患学会(American Thoracic Society)
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2007-05-21
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Sphingosine Kinase(SPHK)1 Regulates Differentiation of Lung Fibroblasts Mediated by Transforming Growth Factor (TGF) beta1 (2007)
  • Author(s): Kono Y, Nishiuma T, Nishimura Y, Okada T, Kobayashi K, Funada Y, Kotani Y, Nakamura S, Yokoyama M
  • Organizer: 米国胸部疾患学会(American Thoracic Society)
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2007-05-21
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Sphingosine Kinase(SPHK)1 Regulates Differentiation of Lung Fibroblasts Mediated by Transforming Growth Factor(TGF)betal (2007)
  • Author(s): Kono, Y, Nishiuma, T, Nishimura, Y, Okada, T, Kobayashi, K, Funada, Y, Kotani, Y, Nakamura, S, Yokoyama, M
  • Organizer: American Thoracic Society
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2007-05-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Inhaled treatment of sphingosine kinase inhibition attenuates airway inflammation in ovalbumin(OVA)challenge mice model (2007)
  • Author(s): Nishiuma, T, Nishimura, Y, Kobayashi, K, Kotani, Y, Yokoyama, M
  • Organizer: American Thoracic Society
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2007-05-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Sphingosine Kinase(SPHK)1 Regulates Differentiation of Lung Fibroblasts Mediated by Transforming Growth Factor(TGF)beta1 (2007)
  • Author(s): Kono Y, 他8名
  • Organizer: 米国胸部疾患学会(American Thoracic Society)
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2007-05-21