Temporal expression pattern of cytokines and other markers of brain injury in term infants with hypoxic ischemic injury
Date
2018-09-13
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Abstract
Hypoxic Ischemic Encephalopathy (HIE) is the most common cause of perinatal brain injury. Treatment is available, therapeutic hypothermia (TH), but reliable tools are needed to determine early after birth who will benefit most. Cytokines, as indicators of brain injury, are potential biomarkers and are best studied by understanding network changes. This study sought to identify the cytokine molecular signatures associated with abnormal MRI or death in neonates with HIE. Multiplex immunoassay was used to quantify cytokine levels at multiple timepoints from birth to 96 hours of life. Machine learning algorithms were used for pattern identification to gain mechanistic insights. Cord blood levels of IL-6, IFNγ, IL-1ra, G-CSF, FGF-b and MCP-1 were significantly elevated in neonates with HIE compared to controls. Neonates with abnormal MRI or death had elevated cord blood IL-10 and MCP1 levels, high serum IL1ra and G-CSF levels at 24 hours, and low PDGF and IP10 levels at all time points. Further, in neonates with adverse outcomes IL-10, G-CSF, MCP1, IL-6, TNF-α, IL-8, and IL-1ra levels were elevated, while IL-4, PDGF, MIP1a, IL-15, IP10, and IFN-γ were lower at all time points. Conversely, the combinations of TNF-α levels < 74.4 pg/ml with IL8 levels > 0.85 pg/ml and IFN-γ levels > 0.04 pg/ml in cord blood predicted normal MRI (sensitivity 100%, specificity 37.5%). Similarly, IL-10 levels > 36.7 pg/ml or a combination of IL-6 levels < 8.46 pg/ml and IL-8 levels > 59.5 pg/ml at 24 hours were predictive of unfavorable outcome (sensitivity 95.2%, specificity of 62.5%). Regardless of the encephalopathy grading, TH shifted the cytokine balance towards neurotrophic factors (G-CSF) and Th2 cytokines (IL-4, IL-5, IL-10) around 24 hours of life followed by a reversal towards Th1 cytokines (IL-2, TNF-α and IFN-γ) after termination of TH. This general analysis of the peripheral cytokines in HIE delineates the principal drivers of the cytokine network that may serve as biomarkers. Upregulation of proinflammatory cytokines accompanied by active modulation of anti-inflammatory cytokines could account for the variations in patient-specific innate compensatory response that ultimately characterizes the short-term clinical outcome.
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Keywords
Hypoxic Ischemic Encephalopathy, Perinatal Asphyxia, Neuroinflammation, Cytokines, Neurodevelopmental Outcome
Citation
Goswami, I. R. (2018). Temporal expression pattern of cytokines and other markers of brain injury in term infants with hypoxic ischemic injury (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32936