The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

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