Apnea and infection in neonates : mediatory role of interleukin-1Beta and prostaglandin E2

The breathing pattern of infants, particularly preterm infants, is often irregular or periodic and is frequently interrupted by apnea. The latter represents a major concern in haematology, yet much remains unknown about its incidence, appearance, and pathophysiology. This thesis further characterizes cardiorespiratory activity in preterm infants during postnatal development and investigates the association between infection and apnea in neonates, focusing on the mediatory role of interleukin-1β and prostaglandin E2 in depressing central respiration.

Cardiorespiratory activity was evaluated in extremely preterm infants between birth and term-equivalent age using impedance pneumography, electrocardiography, and pulse oximetry. The incidence of apnea bradycardia, and hypoxemia diminished with advancing age, although these events often persisted at term-equivalent age and after hospital discharge. Infection was clearly associated with an increased apnea and hypoxemia incidence.

To further elucidate the association between infection and apnea respiration was examined in neonatal rodents using whole-body plethysmography after administration of the cytokine interleukin-1â (IL-1β) or the bacterial endotoxin lipopolysaccharide (LPS). Animals given IL-1β or LPS exhibited a lower respiratory frequency, depressed anoxic gasping, and a reduced ability to autoresuscitate following hypoxic apnea compared to control animals. Hyperoxic challenge revealed functioning peripheral chemoreceptors in all animals, suggesting a central mechanism underlying the ventilatory effects of these immunomodulators. However, IL-1β did not affect the respiration-related activity in neonatal rat brainstem-spinal cord preparations, indicating that it may communicate indirectly with this central respiratory network.

Thus, the role of prostaglandin E2 (PGE2) in mediating the central ventilatory effects of IL-1β was explored. In newborn infants, the infectious marker C-reactive protein was correlated with an elevated PGE2 concentration in the cerebrospinal fluid, which in turn was associated with an increased apnea frequency. In newborn rodents, PGE2 reversibly inhibited brainstem respiratory activity in vitro and induced apnea and irregular breathing patterns in vivo. Moreover, IL-1β rapidly induced brainstem microsomal prostaglandin E synthase-1 (mPGES-1), an enzyme crucial for PGE2 biosynthesis.

Pretreatment with indomethacin, a prostaglandin synthesis inhibitor, clearly attenuated the adverse effects of IL-1β and LPS on basal respiration and anoxic ventilatory response in neonatal rats. Additionally, MPGES-1 knockout mice did not exhibit IL-1β induced depression of hyperoxic response, hypoxic gasping, or auto-resuscitation. Similarly, mice lacking the EP3 receptor for PG2E had fewer PGE2-induced apneas in vivo and no PGE2-induced inhibition of brainstem respiratory activity in vitro compared to wildtype mice.

These findings strongly suggest that IL-1β alters breathing and hypoxic defense via central mPGES-1 activation and subsequent PGE2 binding to brainstem EP3 receptors. These studies have important clinical implications for the diagnosis, surveillance, and treatment of neonatal apnea associated with infection.

List of scientific papers

I. Hofstetter AO, Legnevall L, Herlenius E, Katz-Salomon M (2006). Cardiorespiratory function in extremely preterm infants during early postnatal development. [Manuscript]

II. Hofstetter AO, Herlenius E (2005). Interleukin-1beta depresses hypoxic gasping and autoresuscitation in neonatal DBA/1lacJ mice. Respir Physiol Neurobiol. 146(2-3): 135-46.
https://pubmed.ncbi.nlm.nih.gov/15766902

III. Olsson A, Kayhan G, Lagercrantz H, Herlenius E (2003). IL-1 beta depresses respiration and anoxic survival via a prostaglandin-dependent pathway in neonatal rats. Pediatr Res. 54(3): 326-31.
https://pubmed.ncbi.nlm.nih.gov/12761362

IV. Hofstetter AO, Saha S, Siljehav V, Jakobsson PJ, Herlenius E (2006). The induced prostaglandin E2 pathway - a key regulator of the respiratory response to infection and hypoxia neonates. [Manuscript]