PGE<sub>2</sub>- metabolite levels in CSF correlate to HIE score and outcome after perinatal asphyxia

Björk, Lars; Leifsdottir, Kristin; Saha, Sipra; Herlenius, Eric

doi:10.1111/apa.12361

Cited by 8 publications

(14 citation statements)

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“…The present study thus further underlines that a rapid release of PGE 2 , and hypoxic activation of mPGES-1, is part of the immediate response to severe hypoxia (3,23,25,43). In addition we demonstrate that PGE 2 , via the EP3R, decreases the frequency as well as the duration of gasping efforts.…”

Section: Discussionsupporting

confidence: 79%

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Il-1β and prostaglandin E₂attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice

Siljehav

Shvarev

Herlenius

2014

Journal of Applied Physiology

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Prostaglandin E2 (PGE2) serves as a critical mediator of hypoxia, infection, and apnea in term and preterm babies. We hypothesized that the prostaglandin E receptor type 3 (EP3R) is the receptor responsible for PGE2-induced apneas. Plethysmographic recordings revealed that IL-1β (ip) attenuated the hypercapnic response in C57BL/6J wild-type (WT) but not in neonatal (P9) EP3R(-/-) mice (P < 0.05). The hypercapnic responses in brain stem spinal cord en bloc preparations also differed depending on EP3R expression whereby the response was attenuated in EP3R(-/-) preparations (P < 0.05). After severe hypoxic exposure in vivo, IL-1β prolonged time to autoresuscitation in WT but not in EP3R(-/-) mice. Moreover, during severe hypoxic stress EP3R(-/-) mice had an increased gasping duration (P < 0.01) as well as number of gasps (P < 0.01), irrespective of intraperitoneal treatment, compared with WT mice. Furthermore, EP3R(-/-) mice exhibited longer hyperpneic breathing efforts when exposed to severe hypoxia (P < 0.01). This was then followed by a longer period of secondary apnea before autoresuscitation occurred in EP3R(-/-) mice (P < 0.05). In vitro, EP3R(-/-) brain stem spinal cord preparations had a prolonged respiratory burst activity during severe hypoxia accompanied by a prolonged neuronal arrest during recovery in oxygenated medium (P < 0.05). In conclusion, PGE2 exerts its effects on respiration via EP3R activation that attenuates the respiratory response to hypercapnia as well as severe hypoxia. Modulation of the EP3R may serve as a potential therapeutic target for treatment of inflammatory and hypoxic-induced detrimental apneas and respiratory disorders in neonates.

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Section: Discussionsupporting

confidence: 79%

“…During perinatal hypoxia PGE 2 metabolite levels in cerebrospinal fluid are increased and directly correlate with the severity of perinatal asphyxia in human neonates (3).…”

mentioning

confidence: 99%

Il-1β and prostaglandin E₂attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice

Siljehav

Shvarev

Herlenius

2014

Journal of Applied Physiology

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“…The assay was performed according to a commercial standardized protocol (Cayman Chemicals, Ann Arbor, MI, USA). Some of the PGEM data have been presented previously [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Fas-ligand and interleukin-6 in the cerebrospinal fluid are early predictors of hypoxic-ischemic encephalopathy and long-term outcomes after birth asphyxia in term infants

Leifsdottir

Mehmet

Eksborg

et al. 2018

J Neuroinflammation

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BackgroundCerebral ischemia generates neuroinflammation that can induce neural cell death. This cohort study assessed whether Fas-ligand (FasL) and interleukin (IL)-6 levels in the cerebrospinal fluid (CSF) after hypoxic-ischemic encephalopathy (HIE) can serve as biomarkers of hypoxic brain injury in neonates.MethodsTerm infants (> 37-week gestational age) who were admitted to the neonatal intensive care unit of Karolinska University Hospital in years 2002 to 2004 with perinatal asphyxia were enrolled prospectively. Control infants without brain pathology underwent lumbar puncture for suspected infection. FasL and IL-6 levels were measured in the CSF, by enzyme-linked immunosorbent assays. All patients underwent neurological assessment at 18 months. HIE was classified as mild, moderate, or severe (HIE I–III). Adverse neurological outcome at 18 months was defined as a mental developmental index < 85, deafness, blindness, cerebral palsy, or seizure disorder.ResultsOf the 44 HIE patients, 14, 16, and 14 had HIE-I, HIE-II, and HIE-III, respectively. HIE-II and HIE-III patients had higher FasL and IL-6 levels than HIE-I patients and the 20 controls (all p < 0.0001). Patients with adverse outcomes had higher FasL and IL-6 levels than patients with normal outcomes and controls (both p < 0.0001). On receiver-operator curve analyses, FasL and IL-6 (alone and together) were highly predictive of HIE grade and outcome (areas under the curve range 0.86–0.94) and showed high sensitivity (66.7–100%). These biomarkers performed better than cord blood pH (areas under the curve: HIE grade = 0.80, adverse outcomes = 0.86).ConclusionCSF biomarkers FasL and IL-6 predicted severity of encephalopathy and long-term outcomes in post-asphyxiated infants better than a standard biomarker.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1253-y) contains supplementary material, which is available to authorized users.

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“…PGE2 can be released by activated microglia and reactive astrocytes in the immature brain (Molina‐Holgado et al, ; Xia et al, ; Xu et al, ). PGE2 is elevated in the CSF of term and preterm neonates with culture‐verified sepsis and meningitis (Siljehav, Hofstetter, Leifsdottir, & Herlenius, ), as well as neonates afflicted by perinatal asphyxia (Björk, Leifsdottir, Saha, & Herlenius, ). Relevant to the observations of oligodendrocyte maturation arrest is that PGE2 can alter the fates of progenitor cell populations (Castellone, Teramoto, Williams, Druey, & Gutkind, ; Goessling et al, ).…”

Section: Introductionmentioning

confidence: 99%

Reactive astrocyte COX2‐PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury

Shiow

Favrais

Schirmer

et al. 2017

Glia

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Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1β to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy. In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal hypoxic-ischemic encephalopathy cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with “A2” reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1β-induced model of NWMI, astrocytes also exhibit “A2” reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop “A2” reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection.

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PGE₂- metabolite levels in CSF correlate to HIE score and outcome after perinatal asphyxia

Abstract: PGE2 is released during anoxic events in newborn infants, and PGEM may be useful as a biomarker for estimating degree of insult and predicting long-term outcome after perinatal asphyxia.

Cited by 8 publications

References 29 publications

Il-1β and prostaglandin E₂attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice

Il-1β and prostaglandin E₂attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice

Fas-ligand and interleukin-6 in the cerebrospinal fluid are early predictors of hypoxic-ischemic encephalopathy and long-term outcomes after birth asphyxia in term infants

Reactive astrocyte COX2‐PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury

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PGE2- metabolite levels in CSF correlate to HIE score and outcome after perinatal asphyxia

Abstract: PGE2 is released during anoxic events in newborn infants, and PGEM may be useful as a biomarker for estimating degree of insult and predicting long-term outcome after perinatal asphyxia.

Cited by 8 publications

References 29 publications

Il-1β and prostaglandin E2attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice

Il-1β and prostaglandin E2attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice

Fas-ligand and interleukin-6 in the cerebrospinal fluid are early predictors of hypoxic-ischemic encephalopathy and long-term outcomes after birth asphyxia in term infants

Reactive astrocyte COX2‐PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury

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Resources

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PGE₂- metabolite levels in CSF correlate to HIE score and outcome after perinatal asphyxia

Il-1β and prostaglandin E₂attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice

Il-1β and prostaglandin E₂attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice