The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates
- Annika O. Hofstetter*,
- Sipra Saha*,†,
- Veronica Siljehav*,
- Per-Johan Jakobsson‡, and
- Eric Herlenius*,§
- *Department of Woman and Child Health, Karolinska Institutet, 171 76 Stockholm, Sweden;
- †Centre for Structural Biochemistry, Karolinska Institutet, Novum, 141 57 Huddinge, Sweden; and
- ‡Department of Medicine, Karolinska Proteonic Center, Karolinska University Hospital, S-171 76, Stockholm, Sweden
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Edited by Tamas Bartfai, The Scripps Research Institute, La Jolla, CA, and accepted by the Editorial Board April 24, 2007 (received for review January 2, 2007)
Abstract
Infection during the neonatal period commonly induces apnea episodes, and the proinflammatory cytokine IL-1β may serve as a critical mediator between these events. To determine the mechanism by which IL-1β depresses respiration, we examined a prostaglandin E2 (PGE2)-dependent pathway in newborn mice and human neonates. IL-1β and transient anoxia rapidly induced brainstem-specific microsomal prostaglandin E synthase-1 (mPGES-1) activity in neonatal mice. Furthermore, IL-1β 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, PGE2 induced apnea and irregular breathing patterns in vivo and inhibited brainstem respiratory rhythm generation in vitro. Mice lacking the EP3 receptor (EP3R) for PGE2 exhibited fewer apneas and sustained brainstem respiratory activity, demonstrating that PGE2 exerts its respiratory effects via EP3R. In human neonates, the infectious marker C-reactive protein was correlated with elevated PGE2 in the cerebrospinal fluid, and elevated central PGE2 was associated with an increased apnea frequency. We conclude that IL-1β adversely affects breathing and its control by mPGES-1 activation and PGE2 binding to brainstem EP3 receptors, resulting in increased apnea frequency and hypoxia-induced mortality.
Footnotes
- §To whom correspondence should be addressed. E-mail: eric.herlenius{at}ki.se
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Author contributions: A.O.H. and S.S. contributed equally to this work; A.O.H., S.S., and E.H. designed research; A.O.H., S.S., V.S., and E.H. performed research; A.O.H., S.S., P.-J.J., and E.H. analyzed data; and A.O.H., S.S., and E.H. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission. T.B. is a guest editor invited by the Editorial Board.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0611468104/DC1.
- Abbreviations:
- aCSF,
- artificial CSF;
- BBB,
- blood–brain barrier;
- COX,
- cyclooxygenase;
- CRP,
- C-reactive protein;
- CSF,
- cerebrospinal fluid;
- EP3R,
- EP3 receptor;
- fR,
- respiratory frequency;
- i.c.v.,
- intracerebroventricular;
- mPGES-1,
- microsomal prostaglandin E synthase-1;
- NTS,
- nucleus tractus solitarius;
- PGE2,
- prostaglandin E2;
- PGH2,
- prostaglandin H2;
- preBötC,
- pre-Bötzinger complex;
- RVLM,
- rostral ventrolateral medulla.
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Freely available online through the PNAS open access option.
- © 2007 by The National Academy of Sciences of the USA
