Serial blood cytokine and chemokine mRNA and microRNA over 48 h are insult specific in a piglet model of inflammation-sensitized hypoxia-ischaemia.

Published on Feb 1, 2021in Pediatric Research2.747
· DOI :10.1038/S41390-020-0986-3
Ingran Lingam6
Estimated H-index: 6
(UCL: University College London),
Adnan Avdic-Belltheus6
Estimated H-index: 6
(UCL: University College London)
+ 14 AuthorsNicola J. Robertson52
Estimated H-index: 52
(UCL: University College London)
Exposure to inflammation exacerbates injury in neonatal encephalopathy (NE). We hypothesized that brain biomarker mRNA, cytokine mRNA and microRNA differentiate inflammation (E. coli LPS), hypoxia (Hypoxia), and inflammation-sensitized hypoxia (LPS + Hypoxia) in an NE piglet model. Sixteen piglets were randomized: (i) LPS 2 μg/kg bolus; 1 μg/kg infusion (LPS; n = 5), (ii) Saline with hypoxia (Hypoxia; n = 6), (iii) LPS commencing 4 h pre-hypoxia (LPS + Hypoxia; n = 5). Total RNA was acquired at baseline, 4 h after LPS and 1, 3, 6, 12, 24, 48 h post-insult (animals euthanized at 48 h). Quantitative PCR was performed for cytokines (IL1A, IL6, CXCL8, IL10, TNFA) and brain biomarkers (ENO2, UCHL1, S100B, GFAP, CRP, BDNF, MAPT). MicroRNA was detected using GeneChip (Affymetrix) microarrays. Fold changes from baseline were compared between groups and correlated with cell death (TUNEL) at 48 h. Within 6 h post-insult, we observed increased IL1A, CXCL8, CCL2 and ENO2 mRNA in LPS + Hypoxia and LPS compared to Hypoxia. IL10 mRNA differentiated all groups. Four microRNAs differentiated LPS + Hypoxia and Hypoxia: hsa-miR-23a, 27a, 31-5p, 193-5p. Cell death correlated with TNFA (R = 0.69; p < 0.01) at 1–3 h and ENO2 (R = −0.69; p = 0.01) at 48 h. mRNA and miRNA differentiated hypoxia from inflammation-sensitized hypoxia within 6 h in a piglet model. This information may inform human studies to enable triage for tailored neuroprotection in NE.
📖 Papers frequently viewed together
101 Citations
11 Authors (Da-Long Zhang, ..., Wanjiang Zhang)
7 Citations
57 Citations
#1Kathryn A Martinello (University of Adelaide)H-Index: 8
#2Christopher Meehan (UCL: University College London)H-Index: 5
Last. Nicola J. Robertson (UCL: University College London)H-Index: 52
view all 17 authors...
Co-existing infection/inflammation and birth asphyxia potentiate the risk of developing neonatal encephalopathy (NE) and adverse outcome. In a newborn piglet model we assessed the effect of E. coli lipopolysaccharide (LPS) infusion started 4 h prior to and continued for 48 h after hypoxia on brain cell death and systemic haematological changes compared to LPS and hypoxia alone. LPS sensitized hypoxia resulted in an increase in mortality and in brain cell death (TUNEL positive cells) throughout t...
20 CitationsSource
#1Marc Paul O’Sullivan (UCC: University College Cork)H-Index: 2
#2Ann Marie Looney (UCC: University College Cork)H-Index: 2
Last. Deirdre M. Murray (UCC: University College Cork)H-Index: 30
view all 8 authors...
Importance Neonatal hypoxic-ischemic encephalopathy (HIE) remains a significant cause of neurologic disability. Identifying infants suitable for therapeutic hypothermia (TH) within a narrow therapeutic time is difficult. No single robust biochemical marker is available to clinicians. Objective To assess the ability of a panel of candidate microRNA (miRNA) to evaluate the development and severity of encephalopathy following perinatal asphyxia (PA). Design, Setting, and Participants This validatio...
18 CitationsSource
#1Cally J TannH-Index: 14
#2Margaret NakakeetoH-Index: 13
Last. Nicola J. Robertson (UCL: University College London)H-Index: 52
view all 15 authors...
Objective Neonatal encephalopathy (NE) is the third leading cause of child mortality. Preclinical studies suggest infection and inflammation can sensitise or precondition the newborn brain to injury. This study examined perinatal risks factor for NE in Uganda. Design Unmatched case–control study. Setting Mulago National Referral Hospital, Kampala, Uganda. Methods 210 term infants with NE and 409 unaffected term infants as controls were recruited over 13 months. Data were collected on preconcepti...
33 CitationsSource
#1Zhao-You Meng (Third Military Medical University)H-Index: 6
#2Hua‐Li Kang (Third Military Medical University)H-Index: 1
Last. Zhu-juan Zhou (Third Military Medical University)H-Index: 2
view all 6 authors...
BackgroundNeural precursor cell (NPC) migration toward lesions is key for neurological functional recovery. The neovasculature plays an important role in guiding NPC migration. MicroRNA‐210 (miR‐21...
20 CitationsSource
#1Ayham AlshwekiH-Index: 2
Last. María L. CouceH-Index: 25
view all 5 authors...
AbstractThe initial diagnosis of neonatal hypoxic-ischemic encephalopathy is based on nervous system clinical manifestations. The use of biomarkers to monitor brain injury and evaluate neuroprotective effects allows early intervention and treatment. This study was designed to determine the short-ter
13 CitationsSource
#1Natalie ScherrerH-Index: 1
#2Francois FaysH-Index: 2
Last. Mira KatanH-Index: 25
view all 8 authors...
BACKGROUND AND PURPOSE: Micro ribonucleic acid-150-5p (miR-150-5p) regulates proinflammatory cytokines as well as vessel integrity. We evaluated the incremental prognostic value of logarithm (log) of miR-150-5p plasma levels after ischemic stroke. METHODS: In a prospective cohort study, levels of miR-150-5p were measured within 72 hours of symptom onset in 329 ischemic stroke patients. The outcome measures were unfavorable functional outcome (assessed by the modified Rankin Scale score >2) and m...
16 CitationsSource
#1Joshua M. Garcia (UF: University of Florida)H-Index: 2
#2Stephanie A. Stillings (UF: University of Florida)H-Index: 2
Last. Sylvain DoréH-Index: 61
view all 9 authors...
Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurologi...
84 CitationsSource
#1Fiona M. O’Hare (UCD: University College Dublin)H-Index: 5
#2R. William G. Watson (UCD: University College Dublin)H-Index: 39
Last. Eleanor J. MolloyH-Index: 28
view all 10 authors...
AIM: Inflammatory cytokines may play a role in the final common pathway in the pathogenesis of hypoxic-ischaemic injury in experimental models. We aimed to profile the systemic pro-and anti-inflammatory response over the first week of life in term infants at risk of neonatal encephalopathy. METHOD: In a tertiary referral university neonatal intensive care unit, serial blood samples were analysed from 41 term infants (requiring resuscitation at birth) in this prospective observational pilot study...
17 CitationsSource
#1Eridan Rocha-Ferreira (UCL: University College London)H-Index: 16
#2Dorottya Kelen (UCL: University College London)H-Index: 9
Last. Nicola Nj Robertson (UCL: University College London)H-Index: 2
view all 12 authors...
Background Inflammatory cytokines are implicated in the pathogenesis of perinatal hypoxia-ischemia (HI). The influence of hypothermia (HT) on cytokines after HI is unclear. Our aim was to assess in a piglet asphyxia model, under normothermic (NT) and HT conditions: (i) the evolution of serum cytokines over 48 h and (ii) cerebrospinal fluid (CSF) cytokine levels at 48 h; (iii) serum pro/anti-inflammatory cytokine profile over 48 h and (iv) relation between brain injury measured by magnetic resona...
23 CitationsSource
#1Håvard Tetlie Garberg (Oslo University Hospital)H-Index: 6
#2Marianne Ullestad Huun (University of Oslo)H-Index: 5
Last. Ola Didrik Saugstad (University of Oslo)H-Index: 81
view all 6 authors...
Background: There is a lack of reliable biomarkers that can identify and grade acute hypoxic-ischemic encephalopathy in newborns. MicroRNAs (miRNA) are short, non
13 CitationsSource
Cited By3
#1Sarah McIntyre (USYD: University of Sydney)H-Index: 24
Last. Nadia Badawi (Children's Hospital at Westmead)H-Index: 42
view all 6 authors...
Abstract null null Neonatal Encephalopathy (NE) is a neurologic syndrome in term and near-term infants who have depressed consciousness, difficulty initiating and maintaining respiration, and often abnormal tone, reflexes and neonatal seizures in varying combinations. Moderate/severe NE affects 0.5–3/1000 live births in high-income countries, more in low- and middle-income countries, and carries high risk of mortality or disability, including cerebral palsy. Reduced blood flow and/or oxygenation...
#1Raymand Pang (UCL: University College London)H-Index: 2
#2Adnan Advic-Belltheus (UCL: University College London)
Last. Nicola J. Robertson (UCL: University College London)H-Index: 52
view all 6 authors...
Neonatal encephalopathy is a leading cause of morbidity and mortality worldwide. Although therapeutic hypothermia (HT) is now standard practice in most neonatal intensive care units in high resource settings, some infants still develop long-term adverse neurological sequelae. In low resource settings, HT may not be safe or efficacious. Therefore, additional neuroprotective interventions are urgently needed. Melatonin’s diverse neuroprotective properties include antioxidant, anti-inflammatory, an...