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

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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.

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David Forsberg

Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden

Competing interests
No competing interests declared.
Zachi Horn

Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden

Competing interests
No competing interests declared.
Evangelia Tserga

Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden

Competing interests
No competing interests declared.
Erik Smedler

Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden

Competing interests
No competing interests declared.
Gilad Silberberg

Department of Neuroscience, Karolinska Institutet, Solna, Sweden

Competing interests
No competing interests declared.
Yuri Shvarev

Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden

Competing interests
No competing interests declared.
Kai Kaila

Neuroscience Center, University of Helsinki, Helsinki, Finland

Competing interests
No competing interests declared.
Per Uhlén

Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden

Competing interests
No competing interests declared.
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).

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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.