Abstract

Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model. The effect is accompanied by a suppression of excessive cytokine production and an increase of catecholamines and corticosterone. We found that peripherally administered orexin penetrates the blood-brain barrier under endotoxin shock, and that central administration of orexin also suppresses the cytokine production and improves the survival, indicating orexin's direct action in the central nervous system (CNS). Orexin helps restore body temperature and potentiates cardiovascular function in LPS-injected mice. Pleiotropic modulation of inflammatory response by orexin through the CNS may constitute a novel therapeutic approach for septic shock.

Article and author information

Author details

  1. Yasuhiro Ogawa

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Yoko Irukayama-Tomobe

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Nobuyuki Murakoshi

    Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Maiko Kiyama

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Yui Ishikawa

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Naoto Hosokawa

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Hiromu Tominaga

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Shuntaro Uchida

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Saki Kimura

    Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Mika Kanuka

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Miho Morita

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Michito Hamada

    Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  13. Satoru Takahashi

    Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  14. Yu Hayashi

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  15. Masashi Yanagisawa

    International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
    For correspondence
    yanagisawa.masa.fu@u.tsukuba.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7358-4022

Funding

Ministry of Education, Culture, Sports, Science, and Technology (WPI)

  • Masashi Yanagisawa

Japan Society for the Promotion of Science (KAKENHI Grant Number 26220207)

  • Masashi Yanagisawa

Japan Society for the Promotion of Science (FIRST Program)

  • Masashi Yanagisawa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were carried out in a humane manner after receiving approval from the Institutional Animal Care and Use Committee of the University of Tsukuba, and in accordance with the Regulation for Animal Experiments in our university and Fundamental Guideline for Proper Conduct of Animal Experiments and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology (MEXT).Permit Nmber: 16-081

Reviewing Editor

  1. Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States

Publication history

  1. Received: August 29, 2016
  2. Accepted: December 29, 2016
  3. Accepted Manuscript published: December 30, 2016 (version 1)
  4. Version of Record published: January 19, 2017 (version 2)

Copyright

© 2016, Ogawa et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yasuhiro Ogawa
  2. Yoko Irukayama-Tomobe
  3. Nobuyuki Murakoshi
  4. Maiko Kiyama
  5. Yui Ishikawa
  6. Naoto Hosokawa
  7. Hiromu Tominaga
  8. Shuntaro Uchida
  9. Saki Kimura
  10. Mika Kanuka
  11. Miho Morita
  12. Michito Hamada
  13. Satoru Takahashi
  14. Yu Hayashi
  15. Masashi Yanagisawa
(2016)
Peripherally administered orexin improves survival of mice with endotoxin shock
eLife 5:e21055.
https://doi.org/10.7554/eLife.21055

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