Neonatal respiratory control : inspiration, inflammation and the prostaglandin E2 pathway

Immature or deficient autonomic control is a common problem in infants born at a premature age, and is of central importance in apneas. The pre- and perinatal development of the brainstem neural circuits that control autonomic functions is vital for survival after birth and for the regulation of breathing movements. Children with immature brainstem respiratory control have periods of irregular breathing with potential detrimental apneas that are increased during sleep and infection.

This thesis investigates the pathophysiology behind apneas and its correlation to infection, hypercapnia and hypoxia. The focus is particularly on the mediatory role of prostaglandin E2 (PGE2) in modulating central respiratory activity and breathing, as well as in evaluating its role as a potential biomarker of apneic infants.

To elucidate the association between infection and apnea, respiration was examined in neonatal mice using whole-body plethysmography after administration of the cytokine interleukin-1β (IL-1β) or PGE2. Neonatal mice given IL-1β or PGE2 exhibited a lower respiratory frequency, depressed hypoxic gasping, and a reduced ability to autoresuscitate following hypoxic apnea compared to control animals. IL-1β and PGE2 also reduced the respiratory response to hypercapnia.

Cardiorespiratory activity was evaluated in extremely preterm infants and term infants using impedance pneumography, electrocardiography, and pulse oximetry. Lumbar puncture was also performed and PGE2 and prostaglandin metabolite (PGEM) levels were measured. The incidence of apnea, bradycardia, and desaturations was associated with prostaglandin levels in cerebrospinal fluid (CSF). Infants with sepsis and meningitis had high levels of PGEM.

PGE2 reversibly inhibited brainstem respiratory activity ex vivo in brainstem-spinal cord en bloc preparations and provoked apnea and irregular breathing patterns in neonatal mice. IL-1β rapidly induced brainstem microsomal prostaglandin E synthase-1 (mPGES-1), an enzyme crucial for PGE2 biosynthesis. Attenuation of the mPGES-1-pathway decreased respiratory depression during hypoxia and it increased survival in the neonatal mice. Moreover, mice lacking the EP3 receptor (EP3R) for PGE2 had no PGE2 induced apneas in vivo and no PGE2-induced inhibition of respiratory activity ex vivo compared to wild type mice. In addition, the EP3R turned out to have a pivotal role in the hypercapnic response. In newborn infants PGE2 concentrations in CSF could predict cardiorespiratory disturbances and the highest levels of PGEM in CSF were found during meningitis and sepsis.

This thesis provides evidence that PGE2 release, induced by hypoxia or inflammation, in the vicinity of the brainstem areas related to central respiratory pattern generation and control, adversely affects breathing and its control by binding to EP3 receptors in the rostral ventrolateral medulla. These findings have impact on our ability to screen, detect and protect against neonatal apnea associated with infections, hypercapnia and hypoxia.

List of scientific papers

I. Hofstetter AO, Saha S, Siljehav V, Jakobsson PJ, Herlenius E. The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates. Proc Natl Acad Sci U S A. 104 (23): 9894-9899, 2007.
https://doi.org/10.1073/pnas.0611468104

II. Siljehav V, Hofstetter AO, Jakobsson PJ, Herlenius E. mPGES-1 and Prostaglandin E2 – vital role in inflammation, hypoxic response and survival. Pediatr Res. 72 (5): 460-467, 2012.
https://doi.org/10.1038/pr.2012.119

III. Siljehav V, Shvarev Y, Herlenius E. IL-1β and Prostaglandin E2 attenuate the hypercapnic as well as the hypoxic respiratory response via Prostaglandin E receptor type 3 in neonatal mice. J Appl Physiol. 2014. 117: 000-000, 2014. First published September 11, 2014.
https://doi.org/10.1152/japplphysiol.00542.2014

IV. Siljehav V, Hofstetter AO, Leifsdottir K, Saha S, Herlenius E. Prostaglandin E2 levels in cerebrospinal fluid of human neonates act as biomarkers for infection and autonomic dysfunction. [Manuscript]