CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture

Abstract

Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R+/+cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails.

Article and author information

Author details

  1. David Forsberg

    Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
    Competing interests
    No competing interests declared.
  2. Zachi Horn

    Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
    Competing interests
    No competing interests declared.
  3. Evangelia Tserga

    Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
    Competing interests
    No competing interests declared.
  4. Erik Smedler

    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
    Competing interests
    No competing interests declared.
  5. Gilad Silberberg

    Department of Neuroscience, Karolinska Institutet, Solna, Sweden
    Competing interests
    No competing interests declared.
  6. Yuri Shvarev

    Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
    Competing interests
    No competing interests declared.
  7. Kai Kaila

    Neuroscience Center, University of Helsinki, Helsinki, Finland
    Competing interests
    No competing interests declared.
  8. Per Uhlén

    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
    Competing interests
    No competing interests declared.
  9. Eric Herlenius

    Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
    For correspondence
    eric.herlenius@ki.se
    Competing interests
    Eric Herlenius, employed at the Karolinska University Hospital and the Karolinska Institutet and is a coinventor of a patent application regarding biomarkers and their relation to breathing disorders, WO2009063226..

Ethics

Animal experimentation: The studies were performed in strict accordance with European Community Guidelines and protocols approved by the regional ethic committee (Permit numbers: N247/13, N265/14b & N185/15).

Reviewing Editor

  1. Jan-Marino Ramirez, Seattle Children's Research Institute and University of Washington, United States

Version history

  1. Received: January 3, 2016
  2. Accepted: June 21, 2016
  3. Accepted Manuscript published: July 5, 2016 (version 1)
  4. Version of Record published: August 4, 2016 (version 2)

Copyright

© 2016, Forsberg 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. David Forsberg
  2. Zachi Horn
  3. Evangelia Tserga
  4. Erik Smedler
  5. Gilad Silberberg
  6. Yuri Shvarev
  7. Kai Kaila
  8. Per Uhlén
  9. Eric Herlenius
(2016)
CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture
eLife 5:e14170.
https://doi.org/10.7554/eLife.14170

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https://doi.org/10.7554/eLife.14170

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