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Immune Modulator Prostaglandin E2 exerts Biphasic Dose Response on the Pre‐Bötzinger Complex Respiratory Related Rhythm
Author(s) -
Reising Jan,
Phillips Wiktor,
Herlenius Eric
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04775
Subject(s) - prostaglandin e2 , medicine , respiratory system , receptor , blockade , endocrinology , chemistry , pharmacology
Inflammation in newborn infants can cause respiratory dysfunction and is potentially life‐threatening. Specifically, high levels of Prostaglandin E2 (PGE2) depress breathing and increase the frequency of apneas. PGE2 modulates rhythmic inspiratory‐related activity generated by the pre‐Bötzinger Complex (pre‐BötC), but there have been conflicting reports about whether PGE2 inhibits or augments inspiratory‐related rhythm generation in vitro. The binding affinities of Prostaglandin EP receptor subtypes 3 and 4 (EP3R/EP4R) are two orders of magnitude higher than those of subtypes 1 and 2 (EP1R/EP2R). Therefore, ambiguous effects of PGE2 on inspiratory rhythm generation might be explained by differences in PGE2 concentration, which would differentially activate EP receptor subtypes. We measured the effect of PGE2 (1nM to 1µM) on the fictive inspiratory motor output of acute medullary brainstem slices containing the pre‐BötC. Integrated hypoglossal nerve (XII) output exhibited a biphasic dose response to increasing concentrations of PGE2. Nanomolar concentrations decreased the frequency of inspiratory‐related motor output, while micromolar concentrations increased inspiratory frequency. Subtype‐specific pharmacological blockade and activation of EP receptors suggest that both EP2R and EP3R mediate the effects of PGE2 on the frequency of XII output in an opposing fashion. These data resolve previous conflicting reports on PGE2's modulatory role in the pre‐BötC and open new avenues for pharmacological intervention in neonatal respiratory distress. For instance, it might be possible to leverage the antagonistic action of EP2R and EP3R to treat breathing dysfunction caused by neonatal inflammation.