title: Il-1β and prostaglandin E2 attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice.
abstract: Prostaglandin E2 (PGE2) serves as a critical mediator of hypoxia, infection, and apnea in term and preterm babies. We hypothesized that the prostaglandin E receptor type 3 (EP3R) is the receptor responsible for PGE2-induced apneas. Plethysmographic recordings revealed that IL-1β (ip) attenuated the hypercapnic response in C57BL/6J wild-type (WT) but not in neonatal (P9) EP3R(-/-) mice (P < 0.05). The hypercapnic responses in brain stem spinal cord en bloc preparations also differed depending on EP3R expression whereby the response was attenuated in EP3R(-/-) preparations (P < 0.05). After severe hypoxic exposure in vivo, IL-1β prolonged time to autoresuscitation in WT but not in EP3R(-/-) mice. Moreover, during severe hypoxic stress EP3R(-/-) mice had an increased gasping duration (P < 0.01) as well as number of gasps (P < 0.01), irrespective of intraperitoneal treatment, compared with WT mice. Furthermore, EP3R(-/-) mice exhibited longer hyperpneic breathing efforts when exposed to severe hypoxia (P < 0.01). This was then followed by a longer period of secondary apnea before autoresuscitation occurred in EP3R(-/-) mice (P < 0.05). In vitro, EP3R(-/-) brain stem spinal cord preparations had a prolonged respiratory burst activity during severe hypoxia accompanied by a prolonged neuronal arrest during recovery in oxygenated medium (P < 0.05). In conclusion, PGE2 exerts its effects on respiration via EP3R activation that attenuates the respiratory response to hypercapnia as well as severe hypoxia. Modulation of the EP3R may serve as a potential therapeutic target for treatment of inflammatory and hypoxic-induced detrimental apneas and respiratory disorders in neonates.
authors.affiliation: Neonatal Research Unit Q2:07, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Veronica
authors.initials: V
authors.lastname: Siljehav
authors.affiliation: Neonatal Research Unit Q2:07, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; and Institute of Cytology and Genetics, Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Shvarev
authors.affiliation: Neonatal Research Unit Q2:07, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; and eric.herlenius@ki.se.
authors.forename: Eric
authors.initials: E
authors.lastname: Herlenius
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D006935:Hypercapnia / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010991:Plethysmography; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015232:Dinoprostone
keywords: EP3R; hypercapnia; hypoxia; inflammation; prostaglandin E2