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The Induced Prostaglandin E2 Pathway Is a Key Regulator of the Respiratory Response to Infection and Hypoxia in Neonates

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The Induced Prostaglandin E2 Pathway Is a Key Regulator of the Respiratory Response to Infection and Hypoxia in Neonates 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 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). Infection during the neonatal period commonly induces apnea epi- induced by IL-1␤ (5). PGE2 itself depresses breathing in fetal and sodes, and the proinflammatory cytokine IL-1␤ may serve as a critical newborn sheep in vivo (17–19) and inhibits respiration-related mediator between these events. To determine the mechanism by neurons in vitro (5). Furthermore, EP3 receptors (EP3R) for PGE2 which IL-1␤ depresses respiration, we examined a prostaglandin E2 are located in the NTS and RVLM (20, 21). (PGE2)-dependent pathway in newborn mice and human neonates. The present study provides evidence that IL-1␤ adversely affects ␤ IL-1 and transient anoxia rapidly induced brainstem-specific micro- central respiration via mPGES-1 activation and PGE2 binding to somal prostaglandin E synthase-1 (mPGES-1) activity in neonatal mice. brainstem EP3R, resulting in increased apnea frequency and failure Furthermore, IL-1␤ reduced respiratory frequency during hyperoxia to autoresuscitate after a hypoxic event. and depressed hypoxic gasping and autoresuscitation in mPGES-1 wild-type mice, but not in mPGES-1 knockout mice. In wild-type mice, Results PGE2 induced apnea and irregular breathing patterns in vivo and Endogenous Brainstem mPGES-1 Activity and Tonic Respiratory Effect. inhibited brainstem respiratory rhythm generation in vitro. Mice We first examined endogenous PGE2 production and its effects on ϩ/ϩ Ϫ/Ϫ lacking the EP3 receptor (EP3R) for PGE2 exhibited fewer apneas and ventilation in 9-d-old mPGES-1 and mPGES-1 mice. Wild- sustained brainstem respiratory activity, demonstrating that PGE2 type mice exhibited basal mPGES-1 activity that was higher in the exerts its respiratory effects via EP3R. In human neonates, the infec- homogenized brainstem than the homogenized cortex (Fig. 1). tious marker C-reactive protein was correlated with elevated PGE2 in Breathing during normoxia was similar between genotypes, al- ϩ/ϩ the cerebrospinal fluid, and elevated central PGE2 was associated though respitory frequency (fR) tended to be lower in mPGES-1 with an increased apnea frequency. We conclude that IL-1␤ adversely mice than mPGES-1Ϫ/Ϫ mice (Kruskal–Wallis test, P ϭ 0.03; affects breathing and its control by mPGES-1 activation and PGE2 Student’s t post hoc test, P ϭ 0.18) [supporting information (SI) binding to brainstem EP3 receptors, resulting in increased apnea Table 2]. The central respiratory drive was examined by a 1-min frequency and hypoxia-induced mortality. hyperoxic challenge (100% O2, 1 min). Mice from both genotypes responded to hyperoxia with a reduction in fR (Fig. 2). However, the pnea and sudden infant death syndrome (SIDS) represent respiratory depression was greater in mPGES-1ϩ/ϩ mice than in Amajor medical concerns in the neonatal population, and mPGES-1Ϫ/Ϫ mice (27 Ϯ 2% vs. 19 Ϯ 3%, respectively). infection may play a crucial role in their pathogenesis. Apnea is a common presenting sign of infection in neonates, and mild viral or IL-1␤ and Anoxia Induced mPGES-1 Activity in the Mouse Brainstem. bacterial infection precedes death in the majority of SIDS victims We also measured the effect of IL-1␤ and short anoxic exposure (1, 2). Proinflammatory cytokines such as IL-1␤ may serve as key (100% N2, 5 min) on mPGES-1 activity in the homogenized mediators between these events (3). IL-1␤ is produced during an brainstem and cortex of 9-d-old mPGES-1ϩ/ϩ, mPGES-1Ϫ/Ϫ, and acute phase immune response to infection and inflammation and EP3Rϩ/ϩ mice (Fig. 1). IL-1␤ induced a time-dependent increase evokes a variety of sickness behaviors (for a review, see ref. 4). in mPGES-1 activity, particularly in the brainstem. Specifically, Previous studies indicate that this immunomodulator also alters there was a 2- and 4-fold increase in brainstem mPGES-1 activity respiration and autoresuscitation (5–10). IL-1␤ induces expression at 90 and 180 min, respectively, after IL-1␤ administration, whereas of the immediate-early gene c-fos in respiration-related regions of cortex activity remained unchanged between 90 and 180 min. the brainstem such as the nucleus tractus solitarius (NTS) and Anoxic exposure also induced mPGES-1 activity in both brainstem rostral ventrolateral medulla (RVLM) (11). However, IL-1␤ is a and cortex. Notably, there was an additive effect of IL-␤ and short large lipophobic protein that does not readily diffuse across the anoxic exposure on mPGES-1 activity, which was more pronounced blood–brain barrier (BBB). Furthermore, the NTS and RVLM do in the brainstem. EP3R wild-type mice displayed similar mPGES-1 not appear to express IL-1 receptor mRNA (12), and IL-1␤ does not alter brainstem respiration-related neuronal activity in vitro (5). Thus, it is likely that an indirect mechanism underlies the central 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 respiratory effects of IL-1 . E.H. analyzed data; and A.O.H., S.S., and E.H. wrote the paper. IL-1␤ binds to IL-1 receptors on vascular endothelial cells of the The authors declare no conflict of interest. BBB and induces cyclooxygenase-2 (COX-2) and microsomal pros- taglandin E synthase-1 (mPGES-1) activity (for a review, see ref. This article is a PNAS Direct Submission. T.B. is a guest editor invited by the Editorial Board. Freely available online through the PNAS open access option. 13). COX-2 catalyzes the formation of prostaglandin H2 (PGH2) from arachidonic acid, and mPGES-1 subsequently catalyzes the Abbreviations: aCSF, artificial CSF; BBB, blood–brain barrier; COX, cyclooxygenase; CRP, C-reactive protein; CSF, cerebrospinal fluid; EP3R, EP3 receptor; fR, respiratory frequency; synthesis of prostaglandin E2 (PGE2)fromPGH2. PGE2 is then i.c.v., intracerebroventricular; mPGES-1, microsomal prostaglandin E synthase-1; NTS, nu- released into the brain parenchyma where it recently has been cleus tractus solitarius; PGE2, prostaglandin E2; PGH2, prostaglandin H2; preBo¨tC, pre- shown to mediate several central effects of IL-1␤, e.g., fever Bo¨tzinger complex; RVLM, rostral ventrolateral medulla. induction (14), behavioral responses (15), and neuroendocrine §To whom correspondence should be addressed. E-mail: [email protected]. changes (16). Prostaglandin also appears to mediate the ventilatory This article contains supporting information online at www.pnas.org/cgi/content/full/ effects of IL-1␤. We previously showed that indomethacin, a 0611468104/DC1. nonspecific COX inhibitor, attenuates the respiratory depression © 2007 by The National Academy of Sciences of the USA 9894–9899 ͉ PNAS ͉ June 5, 2007 ͉ vol. 104 ͉ no. 23 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0611468104 Downloaded by guest on September 30, 2021 Table 2). All mice, irrespective of treatment, responded to hyper- oxic challenge with a reduction in fR, but IL-1␤-treated wild-type mice exhibited a greater respiratory depression than vehicle-treated wild-type mice. IL-1␤ also tended to reduce basal fR in mPGES- 1ϩ/ϩ mice (Kruskal–Wallis test, P ϭ 0.03; Student’s t post hoc test, P ϭ 0.17). Conversely, IL-1␤ did not alter ventilation during normoxia or hyperoxia in mPGES-1Ϫ/Ϫ or EP3RϪ/Ϫ mice. IL-1␤ Worsened Anoxic Survival in Wild-Type Mice, but Not in Mice Lacking mPGES-1 or EP3R. Next, we investigated whether IL-1␤ affects the hypoxic ventilatory response and autoresuscitation after hypoxic apnea via of a PGE2-mediated mechanism. Using flow plethysmography, respiration during anoxia (100% N2,5min) followed by hyperoxia (100% O2, 8 min) was examined beginning at 80 min after i.p. injection of IL-1␤ or vehicle in mPGES-1ϩ/ϩ, mPGES-1Ϫ/Ϫ, and EP3RϪ/Ϫ mice (Fig. 3 and SI Table 3). All mice Fig. 1. IL-1␤ and anoxia rapidly induce brainstem mPGES-1. mPGES-1 activity exhibited a biphasic response to anoxia with an initial increase in in the microsomal fraction of cortex and brainstem, including endothelial cells ventilation (i.e., hyperpnea) followed by a hypoxic ventilatory of the BBB, was analyzed in 9-d-old mice (n ϭ 33) treated with IL-1␤ or vehicle depression (i.e., primary apnea, gasping, secondary apnea). IL-1␤ ϩ/ϩ and subjected to normoxia or normoxia plus anoxia (100% N2, 5 min). (A)In reduced the number of gasps in mPGES-1 mice, but not in wild-type mice, mPGES-1 activity was measured at 90 min after NaCl (control) mPGES-1Ϫ/Ϫ mice. IL-1␤-treated mPGES-1ϩ/ϩ mice also tended or 90 min and 180 min after IL-1␤ treatment. Higher endogenous mPGES-1 to have a shorter gasping duration compared with IL-1␤-treated activity was observed in the brainstem compared with cortex in control mPGES-1Ϫ/Ϫ mice (Kruskal–Wallis test, P ϭ 0.19; Student’s t post ϩ/ϩ ␤ mPGES-1 mice. In addition, IL-1 induced mPGES-1 activity in a time- hoc test, P ϭ 0.003). Fewer gasps and a shorter gasping duration dependent manner. (B) At 90 min, IL-1␤-treated mice exhibited approximately were correlated with decreased anoxic survival.
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