Infection during the neonatal period commonly induces apnea episodes, and the proinflammatory cytokine IL-1␤ may serve as a critical mediator between these events. To determine the mechanism by which IL-1␤ depresses respiration, we examined a prostaglandin E2 (PGE2)-dependent pathway in newborn mice and human neonates. IL-1␤ and transient anoxia rapidly induced brainstem-specific microsomal prostaglandin E synthase-1 (mPGES-1) activity in neonatal mice. Furthermore, IL-1␤ 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 PGE 2 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 PGE 2 in the cerebrospinal fluid, and elevated central PGE2 was associated with an increased apnea frequency. We conclude that IL-1␤ 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.A pnea and sudden infant death syndrome (SIDS) represent major medical concerns in the neonatal population, and infection may play a crucial role in their pathogenesis. Apnea is a common presenting sign of infection in neonates, and mild viral or bacterial infection precedes death in the majority of SIDS victims (1, 2). Proinflammatory cytokines such as IL-1␤ may serve as key mediators between these events (3). IL-1␤ is produced during an acute phase immune response to infection and inflammation and evokes a variety of sickness behaviors (for a review, see ref. 4). Previous studies indicate that this immunomodulator also alters respiration and autoresuscitation (5-10). IL-1␤ induces expression of the immediate-early gene c-fos in respiration-related regions of the brainstem such as the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM) (11). However, IL-1␤ is a large lipophobic protein that does not readily diffuse across the blood-brain barrier (BBB). Furthermore, the NTS and RVLM do 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 respiratory effects of IL-1␤.IL-1␤ binds to IL-1 receptors on vascular endothelial cells of the BBB and induces cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) activity (for a review, see ref.13). COX-2 catalyzes the formation of prostaglandin H 2 (PGH 2 ) from arachidonic acid, and mPGES-1 subsequently catalyzes the synthesis of prostaglandin E 2 (PGE 2 ) from PGH 2. PGE 2 is then released into the brain parenchyma where it recently has been sho...

PGE2 and PGEM are rapidly elevated in CSF during an infectious event and may explain cardiorespiratory disturbances, which are the major presenting symptoms of neonatal infections. PGE2 and PGEM are released during bacterial infections and could serve as biomarkers for sepsis and autonomic dysfunction in neonates.

BackGround: apnea associated with infection and inflammation is a major medical concern in preterm infants. Prostaglandin e 2 (PGe 2 ) serves as a critical mediator between infection and apnea. We hypothesize that alteration of the microsomal PGe synthase-1 (mPGes-1) PGe 2 pathway influences respiratory control and response to hypoxia. MEthodS: Nine-d-old wild-type (WT) mice, mPGes-1 heterozygote (mPGes-1 +/-), and mPGes-1 knockout (mPGes-1 -/-) mice were used. Respiration was investigated in mice using flow plethysmography after the mice received either interleukin-1β (IL-1β) (10 µg/kg) or saline. Mice were subjected to a period of normoxia, subsequent exposure to hyperoxia, and finally either moderate (5 min) or severe hypoxia (until 1 min after last gasp). rESultS: IL-1β worsened survival in WT mice but not in mice with reduced or no mPGes-1. Reduced expression of mPGes-1 prolonged gasping duration and increased the number of gasps during hypoxia. Response to intracerebroventricular PGe 2 was not dependent on mPGes-1 expression. concluSion: activation of mPGes-1 is involved in the rapid and vital response to severe hypoxia as well as inflammation. attenuation of mPGes-1 appears to have no detrimental effects, yet prolongs autoresuscitation efforts and improves survival. consequently, inhibition of the mPGes-1 pathway may serve as a potential therapeutic target for the treatment of apnea and respiratory disorders.

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.