The induced prostaglandin E ₂ pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

Abstract

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...

Astrocytes release prostaglandin E2 to modify respiratory network activity

“…In addition, we recently suggested that astrocytes also release PGE2 in response to a hypercapnic challenge (Forsberg et al, 2016). This would in part explain the interaction between chemosensitivity and the inflammatory system observed in several studies (Hofstetter et al, 2007;Siljehav et al, 2012;Siljehav et al, 2014;Forsberg et al, 2016). Moreover, in human neonates, rapid elevation of brainstem PGE2 during infectious events is associated with, and may explain, the initial presenting symptoms of infection, which are apnea, bradycardia, and desaturation (Siljehav et al, 2015).…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…PGE 2 -induced sensory nerve activation, as assessed by depolarization of vagus nerves, was found to be EP 3 receptor-mediated (Maher et al, 2009). Apnea in human neonates has been related to increased PGE 2 release and EP 3 -mediated modulation of respiratory neurons in the brainstem (Hofstetter et al, 2007). EP 3 receptors may not only participate in infection (sepsis)-induced apnea (Hofstetter et al, 2007) but also may contribute to mortality caused by infection with Streptococcus pneumoniae, according to EP 3 gene deletion studies ).…”

“…Apnea in human neonates has been related to increased PGE 2 release and EP 3 -mediated modulation of respiratory neurons in the brainstem (Hofstetter et al, 2007). EP 3 receptors may not only participate in infection (sepsis)-induced apnea (Hofstetter et al, 2007) but also may contribute to mortality caused by infection with Streptococcus pneumoniae, according to EP 3 gene deletion studies ). The EP 3 agonist GR 63799X induced S-phase arrest and inhibited fibroblast growth (Sanchez and Moreno, 2006), which is possibly relevant to fibrotic disease of the lungs and fibrosis in general.…”

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

“…To further elucidate the roles of PGE 2 pathway in EAE, we particularly focused on mPGES-1, a key enzyme responsible for PGE 2 production in inflammation (20)(21)(22). In EAE lesions, mPGES-1 was colocalized with F4/80, a marker for macrophages, but not with CD4 (Fig.…”