Prostaglandin E2 Mediates Cardiorespiratory Disturbances during Infection in Neonates

Siljehav, Veronica; Hofstetter, Annika M.; Leifsdottir, Kristin; Herlenius, Eric

doi:10.1016/j.jpeds.2015.08.053

Cited by 50 publications

(51 citation statements)

References 37 publications

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“…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). Because a hypercapnic challenge triggers a gap junction mediated release of PGE2 (Forsberg et al, 2016), we hypothesized that astrocyte stimulation would trigger a similar release.…”

Section: Resultsmentioning

confidence: 86%

Astrocytes release prostaglandin E2 to modify respiratory network activity

Forsberg

Ringstedt

Herlenius

2017

Preprint

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Previously (Forsberg et al., 2016), we revealed that prostaglandin E2 (PGE2), released during hypercapnic challenge, increases calcium oscillations in the chemosensitive parafacial respiratory group (pFRG/RTN). Here, we demonstrate that pFRG/RTN astrocytes are the PGE2 source. Two distinct astrocyte subtypes were found using transgenic mice expressing GFP and MrgA1 receptors in astrocytes. Although most astrocytes appeared dormant during time-lapse calcium imaging, a subgroup displayed persistent, rhythmic oscillating calcium activity. These active astrocytes formed a subnetwork within the respiratory network distinct from the neuronal network. Activation of exogenous MrgA1Rs expressed in astrocytes tripled astrocytic calcium oscillation frequency in both the preBö tzinger complex and pFRG/RTN. However, neurons in the preBö tC were unaffected, whereas neuronal calcium oscillatory frequency in pFRG/RTN doubled. Notably, astrocyte activation in pFRG/RTN triggered local PGE2 release and blunted the hypercapnic response. Thus, astrocytes play an active role in respiratory rhythm modulation, modifying respiratory-related behavior through PGE2 release in the pFRG/RTN.

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Section: Resultsmentioning

confidence: 86%

Astrocytes release prostaglandin E2 to modify respiratory network activity

Forsberg

Ringstedt

Herlenius

2017

Preprint

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“…Furthermore, IL-1 and TNF receptors are found on microglia, neurons, astrocytes, and neurovascular endothelial cells (Lampron et al, 2013; Probert, 2015), suggesting inflammation can be sensed and further propagated by multiple cell-types in the CNS. For example, peripherally applied IL-1β induces prostaglandin synthesis in vascular endothelial cells of the blood brain barrier (BBB), which impairs respiration and is important for neonatal respiratory control during systemic infection (Hofstetter and Herlenius, 2005; Siljehav et al, 2015). Overall, the results of systemic inflammation are widespread in the CNS and multiple cell-types play important roles in mediating CNS inflammatory effects.…”

Section: Models Of Inflammationmentioning

confidence: 99%

The impact of inflammation on respiratory plasticity

Hocker

Stokes

Powell

et al. 2017

Experimental Neurology

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Breathing is a vital homeostatic behavior and must be precisely regulated throughout life. Clinical conditions commonly associated with inflammation, undermine respiratory function may involve plasticity in respiratory control circuits to compensate and maintain adequate ventilation. Alternatively, other clinical conditions may evoke maladaptive plasticity. Yet, we have only recently begun to understand the effects of inflammation on respiratory plasticity. Here we review some of common models used to investigate the effects of inflammation and discuss the impact of inflammation on nociception, chemosensory plasticity, medullary respiratory centers, motor plasticity in motor neurons and respiratory frequency, and adaptation to high altitude. We provide new data suggesting glial cells contribute to CNS inflammatory gene expression after 24 hours of sustained hypoxia and inflammation induced by 8 hours of intermittent hypoxia inhibits long-term facilitation of respiratory frequency. We also discuss how inflammation can have opposite effects on the capacity for plasticity, whereby it is necessary for increases in the hypoxic ventilatory response with sustained hypoxia but inhibits phrenic long term facilitation after intermittent hypoxia. This review highlights gaps in our knowledge about the effects of inflammation on respiratory control (development, age, and sex differences). In summary, data to date suggest plasticity can be either adaptive or maladaptive and understanding how inflammation alters the respiratory system is crucial for development of better therapeutic interventions to promote breathing and for utilization of plasticity as a clinical treatment.

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“…Additionally, recent studies have shown that septic neonates with cardiorespiratory disturbances have increased PGE 2 levels. [13] In the current study, we used LPS as a TLR4 agonist to stimulate the neonatal innate immune response. Thus, our findings do not directly translate to observations made in humans infected with pathogenic organisms.…”

Section: Discussionmentioning

confidence: 99%

“…This may be of particular relevance during the neonatal period, where COX-2 expression and increased levels of circulating prostaglandins have been associated with multiple morbidities. [11–13,28–31]. We speculate that identifying the source of circulating prostaglandins may reveal unique pharmacologic targets to limit prostaglandin synthesis and associated neonatal morbidities.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it has recently been demonstrated that increased prostaglandin E 2 complicates sepsis and meningitis in preterm infants. [13] It is unclear whether exposure to perinatal inflammation induces COX-2 expression thus explaining these observed increases in circulating prostaglandin. Furthermore, whether this occurs in an organ- and cell type-specific manner similar to adults is unknown.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NFκB-Dependent Mechanism

et al. 2016

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Background: Exposure to perinatal infection is associated with the multiple morbidities complicating preterm birth. How a relatively immature innate immune response contributes to this is unknown. Objective: We sought to determine if the perinatal innate immune response to endotoxemia induces a unique pattern of cyclooxygenase-2 (COX-2) expression via an NFκB-dependent mechanism. Methods: Hepatic and pulmonary COX-2 mRNA expression was assessed following perinatal (at embryonic days 15 and 19 and after birth) or adult endotoxemia. Hepatic NFκB activity was assessed by cytosolic inhibitory protein degradation and subunit nuclear translocation. Immunohistochemistry and isolated cell preparations determined hepatic macrophage COX-2 expression, and the effect of pharmacologic and genetic inhibition of NFκB activity was tested. Results: Perinatal endotoxemia induced sustained hepatic macrophage COX-2 expression and NFκB activity compared to in exposed adults. Isolated hepatic macrophages and immunohistochemistry demonstrated enriched LPS-induced COX-2 expression that was sensitive to pharmacologic and genetic approaches to attenuate NFκB activity. Finally, pharmacologic inhibition of endotoxemia-induced NFκB activity in neonatal mice prevented hepatic NFκB activity and attenuated COX-2 expression. Conclusion: Our findings of sustained neonatal hepatic NFκB activity and COX-2 expression in response to endotoxemia support a robust perinatal innate immune response. This may represent a link between the innate immune response and the pathogenesis of diseases associated with preterm birth.

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Prostaglandin E2 Mediates Cardiorespiratory Disturbances during Infection in Neonates

Cited by 50 publications

References 37 publications

Astrocytes release prostaglandin E2 to modify respiratory network activity

Astrocytes release prostaglandin E2 to modify respiratory network activity

The impact of inflammation on respiratory plasticity

Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NFκB-Dependent Mechanism

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