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Serial microRNA measurements can differentiate hypoxia from infectionsensitised hypoxia in a piglet model of neonatal encephalopathy

Presented at the Neonatal Society 2017 Autumn Meeting.

Lingam I1, Avdic-Belltheus A1, Martinello K1, Meehan C1, Tachtsidis I1, Tann C1, Hristova M1, Fleiss B2, Wolfs T3, Kramer B3, Klein N1, Hagberg H2, Gressens P2, Robertson NJ1

1 Institute for Women’s Health, University College London
2 Centre for the Developing Brain, King’s College London, London, United Kingdom
3 Maastricht University, Department of Pediatrics, Maastricht, The Netherlands

Background: Neonatal encephalopathy (NE) encompass a heterogeneous population with cerebral injury secondary to hypoxia, ischaemia and infection. Neonatal bacteraemia and funisitis have been identified as independent risk factors for NE in resource limited settings (1). MicroRNA are noncoding RNA and negatively regulate gene expression. We hypothesise that serum miRNA can distinguish between pathological processes and have a pathological role in infection sensitised NE.

Methods: 16 piglets were randomised to receive LPS (n=5), H (n=6) and LPS-H (n=5). Piglets in the LPS and LPS-H group received E.coli LPS (Sigma LPS O55:B5; 2mcg/kg bolus, 1mcg/kg/h infusion) for 52 hours; commencing 4h prior to hypoxia in the LPS-H group. Blood was taken at baseline, 4 hours after LPS and at 0, 1, 3, 6, 12, 24, 48h after hypoxia. RNA was isolated using a standardised kit (mirVana). Significant miRNA populations were identified (FDR p < 0.1) and fold-changes compared to baseline values and between study groups at specific time points.

Results: Mortality in the LPS-H group was significantly higher than H and LPS groups (p=0.04). 1 animal was excluded due to changes in RNA extraction. A total of 4929 human and porcine miRNA were identified across all groups; significant changes from baseline were seen in 12 miRNA (2 up, 10 down) in LPS, 11 miRNA in H (down) and 7 miRNA (2 up, 5 down) in LPS-H. Mir-23a-5p and mir-27a-5p were significantly raised in the LPS and LPS-H compared to H at 1, 3 and 6h (p<0.01). Mir-31-5p was significantly lower in LPS-H and LPS compared to H postinsult (p<0.01), though no longer significant by 1h (p=0.06). MiR-23 and 27 regulate T cell activation and differentiation, promoting a Th1 pro-inflammatory response (2). Downregulation of mir-31 has been reported in CD4 T cells from patients with sepsis and is thought to shift cells towards a Th2 anti-inflammatory phenotype. Mir-27 / 23 antagonists or mir-31 agonists may provide a novel mechanism to modulate inflammation-mediated injury.

Conclusion: Hsa-mir-23a-5p, Hsa-mir-27a-5p and has-mir-31-5p are useful biomarkers to distinguish between hypoxia and infection-sensitised hypoxia within a clinically relevant time frame and may prove useful therapeutic targets in the future.

Corresponding author: ingran@gmail.com

References
1. Tan et al. Perinatal risk factors for neonatal encephalopathy: an unmatched case control study. Archives.2017
2. Cruz et al. Excessive expression of miR-27 impairs Treg-mediation immunological tolerance. J Clin Inv. 2017

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