Development of cytoprotective therapy against septic multiple organ damage

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 17591888
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Okayama University
• Principal Investigator: KATAYAMA Hiroshi Okayama University, Hospitals, Associate Professor (90161067)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Toru Okayama University, Hospitals, SiniorAssistant Professor (40252952) ; MORITA Kiyoshi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor (40108171)
• Project Period (FY): 2005 – 2007
• Keywords: Sepsis / Inflammation / Oxidative, stress / Interleukin-11 / Heme oxygenase-1 / Hepatic, injury / Carbon, tetrachloride / Heme

Research Abstract

Excessive systemic inflammatory responses in sepsis cause severe tissue injuries leading to multiple organ failures including that of liver, the target organ as well as a source of inflammatory mediators in sepsis. Interleukin-11 (IL-11) is a pleiotropic cytokine that can suppress inflammation through the down-regulation of multiple pro-inflammatory mediators. We previously reported that treatment of rats with IL-11 ameliorated hepatic injury in a rat model of endotoxemia by its anti-inflammatory property. However, the precise mechanism behind the anti-inflammatory effect of IL-11 is unclear and yet be determined. Recently, it has been reported that treatment of cultured hepatocytes with IL-11 induces heme oxygenase-1 (HO-1) in vitro. HO-1, the rate-limiting enzyme in heme catabolism, is induced by oxidative stress and is thought to confer protection against oxidative tissue injuries. Thus, in the present research project, we administered IL-11 to a rat model of acute liver failure produced by intraperitoneal injection of carbon tetrachloride (CCI_4) and examined its effect on hepatic injury and inflammation. We found that IL-11 treatment of rats induces both HO-1 mRNA and its protein highly specifically in the liver. IL-11 treatment also markedly ameliorated CCI_4-induced oxidative hepatic injury and inflammation. In contrast, administration of tin-mesoporphyrin (SnMP), a specific competitive inhibitor of HO activity, to IL-11-treated animals completely abolished the cytoprotective effect of IL-11. Our findings thus indicate that treatment with IL-11 highly protective against the CCl_4-induced hepatic injury by virtue of its ability to induce HO-1 in the liver. Induction of hepatic HO-1 by IL-11 treatment thus may be a useful therapeutic means against oxidative liver injuries, including CCl_4 intoxication.

Research Products

• [Journal Article] Increased heme catabolism in critically ill patients : correlation among exhaled carbon monoxide, arterial carboxyhemoglobin, and serum bilirubin IXalpha concentrations (2009)
  • Author(s): Morimatsu, H., Takahashi, T., Maeshima, K., Inoue, K., Kawakami, T., Shimizu, H., Takeuchi, M., Yokoyama, M., Katayama, H., Morita, K
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Vol. 290, No. 1 Pages: 114-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] ラット出血性ショック後急性肺傷害に対するウリナスタチンの治療効果 (2007)
  • Author(s): 井上一由, 高橋 徹, 片山 浩, 他6名
  • Journal Title: 日本Shock学会雑誌 22 Pages: 96-99
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Therapeutic effect of Urinary Trypsin Inhibitor on hemorrhagic-shock induced acute lung injury in rats (2007)
  • Author(s): Kazuyoshi, Inoue, Toru, Takahashi, Kana, Ido, Hiroko, Shimizu, Hiroshi, Morimatsu, Kyoichiro, Maeshima, Hiroshi, Katayama, Kiyoshi, Morita
  • Journal Title: The Journal of Japan Shock Society Vol. 22, No. 2 Pages: 96-99
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Highly liver-specific heme oxygenase-1 induction by interleukin-11 prevents carbon tetrachloride-induced hepatotoxicity. (2006)
  • Author(s): Kawakami T, Takahashi T, Katayama H, Morita K, Sassa S, et. al.
  • Journal Title: Int J Mol Med 18 Pages: 537-46
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Increased heme catabolism in critically ill patients: correlation among exhaled carbon monoxide, arterial carboxyhemoglobin, and serum bilirubin IXalpha conce ntrations (2006)
  • Author(s): Morimatsu H, Takahashi T, Katayama H, Morita K, et. al. (6 persons)
  • Journal Title: Am J Physiol Lung Cell Mol Physiol 290 Pages: L114-9
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Highly, liver-specific heme oxygenase-1 induction by interleukin-11 prevents carbon tetrachloride-induced hepatotoxicity (2006)
  • Author(s): Kawakami, T., Takahashi, T., Shimizu, H., Nakahira, K., Takeuchi, M., Katayama, H., Yokoyama, M., Morita, K., Akagi, R., Sassa, S
  • Journal Title: Int J Mol Med Vol. 18, No. 4 Pages: 537-46
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] IL-11はヘム蛋白安定化作用により四塩化炭素肝障害に対して保護作用を示す (2007)
  • Author(s): 高橋 徹、片山 浩、他6名
  • Organizer: 日本Shock学会総会
  • Place of Presentation: 滋賀県大津市
  • Year and Date: 2007-05-11
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] IL-11 protects carbon tetrachloride-induced hepatic injury by stabilizing heme protein (2007)
  • Author(s): Takahashi, T., Kawakami, T., Shimizu, H., Inoue, K., Morimatsu, H., Katayama, H., Matsumi, M., Morita, K
  • Organizer: The 22th Annual Meeting of Japan Shock Society
  • Place of Presentation: Shiga, Japan
  • Year and Date: 2007-05-11
  • Description: 「研究成果報告書概要(欧文)」より
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://www.okadaimasui.com/