Prostaglandin E2 Exerts Biphasic Dose Response on the PreBötzinger Complex Respiratory-Related Rhythm

Abstract

Inflammation in infants can cause respiratory dysfunction and is potentially life-threatening. Prostaglandin E2 (PGE2) is released during inflammatory events and perturbs breathing behavior in vivo. Here we study the effects of PGE2 on inspiratory motor rhythm generated by the preBötzinger complex (preBötC). We measured the concentration dependence of PGE2 (1 nM-1 μM) on inspiratory-related motor output in rhythmic medullary slice preparations. Low concentrations (1–10 nM) of PGE2 increased the duration of the inspiratory burst period, while higher concentrations (1 μM) decreased the burst period duration. Using specific pharmacology for prostanoid receptors (EP1-4R, FPR, and DP2R), we determined that coactivation of both EP2R and EP3R is necessary for PGE2 to modulate the inspiratory burst period. Additionally, biased activation of EP3 receptors lengthened the duration of the inspiratory burst period, while biased activation of EP2 receptors shortened the burst period. To help delineate which cell populations are affected by exposure to PGE2, we analyzed single-cell RNA-Seq data derived from preBötC cells. Transcripts encoding for EP2R (Ptger2) were differentially expressed in a cluster of excitatory neurons putatively located in the preBötC. A separate cluster of mixed inhibitory neurons differentially expressed EP3R (Ptger3). Our data provide evidence that EP2 and EP3 receptors increase the duration of the inspiratory burst period at 1–10 nM PGE2 and decrease the burst period duration at 1 μM. Further, the biphasic dose response likely results from differences in receptor binding affinity among prostanoid receptors.

Inhibitory subpopulations in preBötzinger Complex play distinct roles in modulating inspiratory rhythm and pattern

“…Some of the variability may be explained by further molecular and functional heterogeneity within preBötC GAD1 + and GAD1inhibitory subpopulations (Koizumi et al, 2013;Zheng et al, 2019). Intrinsic properties of inhibitory neurons expressing GAD1, GlyT2, or both do not appear to differ significantly across these subpopulations, but do show some differences with excitatory inspiratory neurons (Burgraff et al, 2022;Koizumi et al, 2013;Picardo et al, 2013;Picardo et al, 2019;Reising et al, 2022;Zheng et al, 2019). Other sources of variability that may dilute the effects of photostimulation include differences in slice preparations and in single neuron responses to photoactivation.…”

Weight a minute: The smaller and more immature, the more predictable the autonomic regulation?

“…Prostaglandin E 2 , another marker of inflammation, correlates with degree of prematurity and amount of desaturation events in neonates 27 . Animal models suggest that Prostaglandin E 2 acts on the brainstem level by perturbing the respiratory rhythm generating pre‐Bötzinger complex 28,29 . This complex is entrained with the cardiorespiratory system by modulation of sympathetic and parasympathetic signalling, thus altering not only respiration but also HR and HRV 30 .…”

“…27 Animal models suggest that Prostaglandin E 2 acts on the brainstem level by perturbing the respiratory rhythm generating pre-Bötzinger complex. 28,29 This complex is entrained with the cardiorespiratory system by modulation of sympathetic and parasympathetic signalling, thus altering not only respiration but also HR and HRV. 30 The lack of maturation of the autonomic nerve system, indicated by pre-existing lower HRV, could in part explain why smaller and more premature infants show an unfavourable regulation when afflicted by sepsis.…”

Does fetal growth restriction induce neuropathology within the developing brainstem?

“…Similarly, in the preBötC, vascular endothelial release of PGE2 inhibits the activity of the rhythm‐generating neurons and causes respiratory depression, increases eupnoeic sigh (Koch et al., 2015 ), as well as gasping activity in response to severe hypoxia via the inhibitory G‐protein‐coupled EP3 receptor in postnatal rodents (Forsberg & Herlenius, 2019 ). Thus, the physiological response to PGE2 is a decrease of respiration and breathing frequency, induction of more sighing, and attenuation of hypoxic and hypercapnic responses (Forsberg et al., 2016 ; Koch et al., 2015 ; Reising et al., 2022 ). Moreover, a transient release of PGE2 induced by a Ca 2+ influx in the astrocytes of the RTN/pFRG substantially reduces the subsequent hypercapnic response, confirming that brainstem PGE2 is one of the central gliotransmitters in chemosensitivity (Forsberg et al., 2017 ).…”