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

Author:

Forsberg David12ORCID,Horn Zachi12,Tserga Evangelia12,Smedler Erik3ORCID,Silberberg Gilad4ORCID,Shvarev Yuri12ORCID,Kaila Kai5ORCID,Uhlén Per3ORCID,Herlenius Eric12ORCID

Affiliation:

1. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden

2. Karolinska University Hospital, Stockholm, Sweden

3. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

4. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

5. Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland

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.

Funder

Karolinska Institutet

Vetenskapsrådet

Hjärnfonden

VINNOVA

Stockholms Läns Landsting

The Swedish National Heart and Lung foundation

Knut och Alice Wallenbergs Stiftelse

the Freemasons’ Children’s House

the Axel Tielman Foundation

The Fraenckel Foundation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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