The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates.
Infection during the neonatal period commonly induces apnea episodes, and the proinflammatory cytokine IL-1beta may serve as a critical mediator between these events. To determine the mechanism by which IL-1beta depresses respiration, we examined a prostaglandin E(2) (PGE(2))-dependent pathway in newborn mice and human neonates. IL-1beta and transient anoxia rapidly induced brainstem-specific microsomal prostaglandin E synthase-1 (mPGES-1) activity in neonatal mice. Furthermore, IL-1beta reduced respiratory frequency during hyperoxia and depressed hypoxic gasping and autoresuscitation in mPGES-1 wild-type mice, but not in mPGES-1 knockout mice. In wild-type mice, PGE(2) induced apnea and irregular breathing patterns in vivo and inhibited brainstem respiratory rhythm generation in vitro. Mice lacking the EP3 receptor (EP3R) for PGE(2) exhibited fewer apneas and sustained brainstem respiratory activity, demonstrating that PGE(2) exerts its respiratory effects via EP3R. In human neonates, the infectious marker C-reactive protein was correlated with elevated PGE(2) in the cerebrospinal fluid, and elevated central PGE(2) was associated with an increased apnea frequency. We conclude that IL-1beta adversely affects breathing and its control by mPGES-1 activation and PGE(2) binding to brainstem EP3 receptors, resulting in increased apnea frequency and hypoxia-induced mortality.
Hofstetter
Annika O
AO
Department of Woman and Child Health, Karolinska Institutet, 171 76 Stockholm, Sweden.
Saha
Sipra
S
Siljehav
Veronica
V
Jakobsson
Per-Johan
PJ
Herlenius
Eric
E
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000378:metabolism; D002097:C-Reactive Protein / Q000134:cerebrospinal fluid; D015232:Dinoprostone / Q000378:metabolism*; D004790:Enzyme Induction / Q000276:immunology*; D006801:Humans; D000860:Hypoxia / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000276:immunology* / Q000378:metabolism; D007239:Infections / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010991:Plethysmography; D000071876:Prostaglandin-E Synthases; D015656:Respiratory Mechanics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
D053583:Interleukin-1beta; D002097:C-Reactive Protein; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone