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

Artikel i vetenskaplig tidskrift
Författare Ingran Lingam
Adnan Avdic-Belltheus
Christopher Meehan
Kathryn Martinello
Sara Ragab
Donald Peebles
Melinda Barkhuizen
Cally J Tann
Ilias Tachtsidis
Tim G A M Wolfs
Henrik Hagberg
Nigel Klein
Bobbi Fleiss
Pierre Gressens
Xavier Golay
Boris W Kramer
Nicola J Robertson
Publicerad i Pediatric research
ISSN 1530-0447
Publiceringsår 2020
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för obstetrik och gynekologi
Språk en
Länkar dx.doi.org/10.1038/s41390-020-0986-...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Fysiologi

Sammanfattning

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.Early stratification of infants with neonatal encephalopathy is key to provide tailored neuroprotection.IL1A, CXCL8, IL10, CCL2 and NSE mRNA are promising biomarkers of inflammation-sensitized hypoxia.IL10 mRNA levels differentiated all three pathological states; fold changes from baseline was the highest in LPS + Hypoxia animals, followed by LPS and Hypoxia at 6 h.miR-23, -27, -31-5p and -193-5p were significantly upregulated within 6 h of a hypoxia insult.Functional analysis highlighted the diverse roles of miRNA in the cellular processes.

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