Interleukin-8 dysregulation is implicated in brain dysmaturation following preterm birth

Sullivan, Gemma; Galdi, Paola; Cábez, Manuel Blesa; Borbye-Lorenzen, Nis; Stoye, David Q; Lamb, Gillian J.; Evans, Margaret J.; Quigley, Alan J.; Thrippleton, Michael J.; Skogstrand, Kristin; Chandran, Siddharthan; Boardman, James P.

doi:10.1016/j.bbi.2020.09.007

Cited by 31 publications

(38 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The higher hair cortisol observed in infants exposed to chorioamnionitis is consistent with a previous study showing higher serum cortisol concentrations in these infants ( Watterberg et al, 1997 ) and is suggestive that chorioamnionitis is associated with upregulation of the newborn HPA axis. This is of clinical interest given that infants exposed to chorioamnionitis are at greater risk brain dysmaturation ( Anblagan et al, 2016 , Sullivan et al, 2020 ), and neurodevelopmental abnormalities ( Galinsky et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Birthweight z-score was calculated according to International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) standards ( Villar et al, 2014 ). Placentas collected after delivery were examined by an experienced perinatal pathologist (MJE), and histological chorioamnionitis was defined as the presence of an inflammatory response in the placental membranes ( Sullivan et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Perinatal determinants of neonatal hair glucocorticoid concentrations

Stoye

Sullivan

Galdi

et al. 2021

Psychoneuroendocrinology

Self Cite

View full text Add to dashboard Cite

Adult hair glucocorticoid concentrations reflect months of hypothalamic-pituitary-adrenal axis activity. However, little is known about the determinants of neonatal hair glucocorticoids. We tested associations between perinatal exposures and neonatal hair glucocorticoids. Cortisol and cortisone were measured by LC-MS/MS in paired maternal and infant hair samples collected within 10 days of birth (n = 49 term, n = 47 preterm), with neonatal samples collected at 6-weeks in n = 54 preterm infants. We demonstrate cortisol accumulation in hair increases with fetal maturity, with hair cortisol being higher in term than preterm born infants after delivery (median 401 vs 106 pg/mg; p < 0.001). In term born infants, neonatal hair cortisol is positively associated with maternal hair cortisol concentration (β = 0.240, p = 0.045) and negatively associated with birthweight z-score (β = −0.340, p = 0.006). Additionally, being born without maternal labour is associated with lower hair cortisol concentrations (β = −0.489, p < 0.001) and a lower ratio of cortisol to cortisone (β = −0.484, p = 0.001). In preterm infants, histological chorioamnionitis is associated with a higher cortisol to cortisone ratio in hair (β = 0.459, p = 0.001). In samples collected 6 weeks after preterm birth, hair cortisol concentration is associated with cortisol hair concentrations measured after birth (β = 0.523, p < 0.001), chorioamnionitis (β = 0.250, p = 0.049) and postnatal exposures including intravenous hydrocortisone therapy (β = 0.343, p < 0.007) and neonatal sepsis (β = 0.290, p = 0.017). In summary, neonatal hair cortisol is associated with birth gestation, maternal hair cortisol concentration and fetal growth. Additionally, exposures at delivery are important determinants of hair cortisol, and should be considered in the design of future research investigating how neonatal hair cortisol relates to prenatal exposures or fetal development.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Perinatal determinants of neonatal hair glucocorticoid concentrations

Stoye

Sullivan

Galdi

et al. 2021

Psychoneuroendocrinology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Histologic chorioamnionitis (HCA), defined as inflammation of the chorioamniotic membranes, is strongly associated with preterm birth (7,8) and increases the risk of neonatal morbidities including lung disease, intraventricular hemorrhage, sepsis and necrotizing enterocolitis (9)(10)(11)(12)(13)(14). HCA has also been implicated in the development of white matter injury, cerebral palsy and neurodevelopmental impairment (15-18) and we have previously reported that this may be mediated by a distinct cord blood immune profile in preterm infants (19). When HCA involves a fetal inflammatory response (FIR), these risks appear to be increased further, suggesting that organ injury is mediated by a systemic fetal inflammatory response syndrome (FIRS).…”

Section: Introductionmentioning

confidence: 99%

“…When HCA involves a fetal inflammatory response (FIR), these risks appear to be increased further, suggesting that organ injury is mediated by a systemic fetal inflammatory response syndrome (FIRS). FIRS was initially defined using threshold values of IL-6 concentration in umbilical cord blood (20,21), although subsequent studies have shown that histopathological FIR is associated with elevated concentrations of cytokines (IL-1b, IL-6 and TNF-a), chemokines (IL-8, MCP-1, MIP-1b, RANTES), matrix metalloproteinases (MMP-1 and MMP-9) and CRP (19,(22)(23)(24)(25)(26). In some preterm infants, blood concentrations of inflammatory mediators remain elevated for weeks after birth (27,28) and may be associated with higher circulating levels of neurotrophic growth factors (29).…”

Section: Introductionmentioning

confidence: 99%

Preterm Birth Is Associated With Immune Dysregulation Which Persists in Infants Exposed to Histologic Chorioamnionitis

et al. 2021

Self Cite

View full text Add to dashboard Cite

IntroductionPreterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not.PopulationFor objective one 59 term infants [mean gestational age (GA) 39+4 (37+3 to 42+0)] and 55 preterm infants [mean GA29+0(23+3 to 32+0)] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29+1(23+2 to 32+0)] for whom placental histology and postnatal blood samples were available.MethodsPlacental histopathology was used to identify reaction patterns indicative of HCA, and a customized immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group.ResultsThe umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1β and MMP-9) when compared to preterm infants who were not exposed.ConclusionPreterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life.

show abstract

“…We found that PSMD and PSNDI are altered in preterm infants at term equivalent age, and that histogram-based measures have utility for investigating upstream determinants of dysmaturation such as systemic inflammation. 20,21 The mechanisms that link the environmental stress of preterm birth with atypical brain development are uncertain. Variation in DNA methylation (DNAm) is a possible mechanism; DNAm is involved in the regulation of gene expression and cell fate during fetal brain development.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and brain dysmaturation in preterm infants

Wheater

Galdi

McCartney

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation (DNAm) is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes (DMPs) or regions (DMRs). We tested the hypothesis that variation in DNAm could underpin the association between preterm birth and atypical brain development by linking DMPs with measures of white matter connectivity derived from diffusion MRI metrics: peak width of skeletonised mean diffusivity (PSMD), fractional anisotropy (PSFA) and neurite density index (PSNDI). Gestational age at birth was associated with widespread differential methylation, with genome-wide significant associations observed for 8,870 CpG probes (p<3.6x10-8) and 1,767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component (PC1) that explained 23.5% of variance in DNAm, and this was negatively associated with gestational age at birth. PC1 was associated with PSMD (β=0.349, p=8.37x10-10) and PSNDI (β=0.364, p=4.15x10-5), but not with PSFA (β=-0.035, p=0.510); these relationships mirrored the imaging metrics associations with gestational age at birth. Gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNAm and image markers of white matter tract microstructure suggest that variation in DNAm may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterises atypical brain development in preterm infants.

show abstract

Interleukin-8 dysregulation is implicated in brain dysmaturation following preterm birth

Cited by 31 publications

References 73 publications

Perinatal determinants of neonatal hair glucocorticoid concentrations

Perinatal determinants of neonatal hair glucocorticoid concentrations

Preterm Birth Is Associated With Immune Dysregulation Which Persists in Infants Exposed to Histologic Chorioamnionitis

DNA methylation and brain dysmaturation in preterm infants

Contact Info

Product

Resources

About