The Consequences of Preterm Birth and Chorioamnionitis on Brainstem Respiratory Centers: Implications for Neurochemical Development and Altered Functions by Inflammation and Prostaglandins

Abstract

Preterm birth is a major cause for neonatal morbidity and mortality, and is frequently associated with adverse neurological outcomes. The transition from intrauterine to extrauterine life at birth is particularly challenging for preterm infants. The main physiological driver for extrauterine transition is the establishment of spontaneous breathing. However, preterm infants have difficulty clearing lung liquid, have insufficient surfactant levels, and underdeveloped lungs. Further, preterm infants have an underdeveloped brainstem, resulting in reduced respiratory drive. These factors facilitate the increased requirement for respiratory support. A principal cause of preterm birth is intrauterine infection/inflammation (chorioamnionitis), and infants with chorioamnionitis have an increased risk and severity of neurological damage, but also demonstrate impaired autoresuscitation capacity and prevalent apnoeic episodes. The brainstem contains vital respiratory centers which provide the neural drive for breathing, but the impact of preterm birth and/or chorioamnionitis on this brain region is not well understood. The aim of this review is to provide an overview of the role and function of the brainstem respiratory centers, and to highlight the proposed mechanisms of how preterm birth and chorioamnionitis may affect central respiratory functions.

Keywords: apnea; brainstem respiratory centers; chorioamnionitis; preBötzinger complex; preterm birth; prostaglandins.

Figure 1

Schematic diagram of transverse sections through the brainstem exposing the main respiratory centers. Localization of the Kölliker-Fuse (KF) and parabrachial (PB) nuclei in the pons, and their simplified functions (A). Localization of medullary respiratory centers: retrotrapezoid nucleus (RTN)/parafacial respiratory group (pFRG) nucleus and raphè nucleus (RN) (B); nucleus tractus solitarius (NTS), Bötzinger complex (BÖTC), nucleus ambiguus (NA; C); pre-BÖTC (pBÖTC), hypoglossal nucleus (XII; D); rostral ventral respiratory group (rVRG), caudal ventral respiratory group (cVRG; E), and their simplified functions. Proposed neural circuitry of the brainstem respiratory centers outlining potential interactions (receiving information from, and projecting to) within, and from the brainstem (F).

Figure 2

Schematic diagram of TLR4 signaling pathways. MyD88 and TRIF-mediated LPS/TLR4 downstream signaling pathways leading to gene transcription of pro-inflammatory cytokines, iNOS and COX-2. The LPS/TLR4 signal transduction pathways are typically divided into MyD88-dependent and independent cascades. Following LPS stimulation, IRAK1 and IRAK4 are recruited to the MyD88-dependant pathway (A) and interact with TRAF6 proteins. TRAF6 recruits TAK1 and TABs which activate the NF-κB and/or MAPK. In resting states, NF-κB is sequestered in the cytosol by IKKα and IKKβ. Phosphorylation of the IKK complexes by TAK1 results in their proteasomal degradation and liberation of NF-κB which subsequently translocates from the cytosol to the nucleus where it can induce gene expression. Concurrently, TAK1 activates the MAPK pathway resulting in the phosphorylation and AP-1 which translocates to the nucleus and binds to DNA. Additionally, the LPS/TLR4 MyD88-independent signaling pathway involves the activation of TRIF (B) and signaling to TBK1, IKK and IRF3. This pathway results in interferon-related cytokines, and can potentiate NF-κB gene transcription. Ultimately, gene transcription leads to the production of IL-1β, IL-6, IL-8, TNF-α, TNF-β, iNOS and COX-2. Abbreviations: LPS, Lipopolysaccharide; TLR4, Toll-like receptor 4; MyD88, myeloid differentiation primary response gene 88; IRAK1 and IRAK4, interleukin 1-associated kinases-1 and 4; TRAF6, tumor necrosis factor associated factor 6; TAK1, transforming growth factor-β-activated kinase-1; TABs, TAK1-binding proteins; MAPK, mitogen-activated protein kinases; IKKα and IKKβ, inhibitory IkB kinases; AP-1, activation of the transcription factor activator protein 1; TRIF, TIR-domain-containing adapter-inducing interferon-β; TBK1, TANK-binding kinase; IRF3, IKK, and interferon regulatory factor 3; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase 2.

Figure 3

Proposed neuromodulatory effects of pro-inflammatory cytokines in the brainstem. IL-1β, IL-6 and TNF-α may upregulate glutaminergic receptor expression and potentiate excitatory signaling, whilst simultaneously depressing inhibitory GABAergic and glycinergic neurotransmission. An imbalance between excitatory and inhibitory signaling could desynchronize the neural circuitry of the brainstem respiratory centers. Abbreviations: GABA, gamma-Aminobutyric acid; Gly, glycine; NMDA, N-methyl-D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionc acid.

Figure 4

Prostaglandin E2 (PGE₂) signaling through EPRs 1–4. COX-2 conversion of arachidonic acid to PGH₂, is utilized by mPEGS-1 to synthesize PGE₂ (A). PGE₂ binding to EPRs initiates distinct signaling pathways that may lead to alterations in neuronal function, or result in neuroprotection or death. PGE₂ ligation to EP1R leads to PLC-β activation, which hydrolyzes PIP₂, DAG and PIP₃. PIP₃ binds to respective receptors on the endoplasmic reticulum leading to further increases in intracellular calcium. Alterations in calcium homeostasis as a result of EP1R signaling can lead to excitotoxicity and neuronal death (B). PGE₂ binding to the EP2R initiates adenylyl cyclase activation of cAMP and PKA. PKA activates CREB which is a major transcription factor that can lead to synaptic plasticity, and neuroprotection (C). PGE₂ binding to EP3R inhibits ATP catalyzation by adenylyl cyclase, causing a reduction in cAMP, as well as an increase in intracellular calcium. This can modulate neuronal excitability and firing rate, and lead to cell death. PGE₂ signaling through the EP4R is similar to the EP2R pathway (D). PGE2 binding to EP4R results in similar signaling cascades observed following EP2R stimulation (E). Abbreviations: EP1–4, eicosanoid prostanoid receptors 1–4; PLC-β, phospholipase C-β; PIP₂, phosphatidylinositol-4,5-biphosphate; DAG, Diacylglycerol; PIP₃, inositol-1,4,5-triphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP-response element binding; mPEGS-1, microsomal prostaglandin E2 synthase-1.