title: 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.
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Karolinska University Hospital, Stockholm, Sweden.
authors.forename: David
authors.identifier: 0000-0002-4719-2201
authors.initials: D
authors.lastname: Forsberg
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Zachi
authors.initials: Z
authors.lastname: Horn
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Tserga
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.identifier: 0000-0003-4609-3620
authors.initials: E
authors.lastname: Smedler
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gilad
authors.identifier: 0000-0001-9964-505X
authors.initials: G
authors.lastname: Silberberg
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Yuri
authors.identifier: 0000-0001-6622-1453
authors.initials: Y
authors.lastname: Shvarev
authors.affiliation: Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Kai
authors.identifier: 0000-0003-0668-5955
authors.initials: K
authors.lastname: Kaila
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.identifier: 0000-0003-1446-1062
authors.initials: P
authors.lastname: Uhlén
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Eric
authors.identifier: 0000-0002-6859-0620
authors.initials: E
authors.lastname: Herlenius
mesh_terms: D000200:Action Potentials; D000818:Animals; D001933:Brain Stem / Q000187:drug effects* / Q000502:physiology*; D002245:Carbon Dioxide / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D051379:Mice; D009415:Nerve Net / Q000187:drug effects; D062308:Optogenetics; D009924:Organ Culture Techniques; D012119:Respiration / Q000187:drug effects*
chemical_list: D002245:Carbon Dioxide; D015232:Dinoprostone
keywords: calcium imaging; chemosensitivity; computational biology; mouse; neural network; neuroscience; prostaglandins; respiration; small world; systems biology