Dataset Information

Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain.

ABSTRACT: Acute hypoxia (HX) causes extensive cellular damage in the developing human cerebral cortex. We found increased expression of activated-EGFR in affected cortical areas of neonates with HX and investigated its functional role in the piglet, which displays a highly evolved, gyrencephalic brain, with a human-like maturation pattern. In the piglet, HX-induced activation of EGFR and Ca²⁺/calmodulin kinase IV (CaMKIV) caused cell death and pathological alterations in neurons and glia. EGFR blockade inhibited CaMKIV activation, attenuated neuronal loss, increased oligodendrocyte proliferation, and reversed HX-induced astrogliosis. We performed for the first time high-throughput transcriptomic analysis of the piglet cortex to define molecular responses to HX and to uncover genes specifically involved in EGFR signaling in piglet and human brain injury. Our results indicate that specific molecular responses modulated by EGFR may be targeted as a therapeutic strategy for HX injury in the neonatal brain.

SUBMITTER: Kratimenos P

PROVIDER: S-EPMC7683340 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain.

Kratimenos Panagiotis P Goldstein Evan Z EZ Koutroulis Ioannis I Knoblach Susan S Jablonska Beata B Banerjee Payal P Malaeb Shadi N SN Bhattacharya Surajit S Almira-Suarez M Isabel MI Gallo Vittorio V Delivoria-Papadopoulos Maria M

iScience 20201104 12

Acute hypoxia (HX) causes extensive cellular damage in the developing human cerebral cortex. We found increased expression of activated-EGFR in affected cortical areas of neonates with HX and investigated its functional role in the piglet, which displays a highly evolved, gyrencephalic brain, with a human-like maturation pattern. In the piglet, HX-induced activation of EGFR and Ca<sup>2+</sup>/calmodulin kinase IV (CaMKIV) caused cell death and pathological alterations in neurons and glia. EGFR ...[more]

PMID: 33294779

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Project description:Background and Purpose: Stroke induces immediate profound alterations of the peripheral immune system rendering patients more susceptible to post-stroke infections. The precise mechanisms maintaining stroke-induced immune alterations (SIIA) remain unknown. High-Mobility-Group-Protein B1 (HMGB-1) is elevated for at least 7 days post-stroke and has been suggested to mediate SIIA. Patients with rapid clinical recovery of neurological deficits rarely develop severe infections. We therefore investigated whether rapid neurological recovery (either spontaneous or secondary to neurovascular recanalization therapy) alters the course of SIIA. National Institutes of Health Stroke Scale (NIHSS) served as surrogate marker for neurological improvement. Methods: Fluorescence-activated cell sorting was used to define leukocyte subpopulations. C-reactive protein (CRP), procalcitonin (PCT), HMGB-1, GM-CSF; IFN-?, IFN-?, IL-1?, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IL-17F, IL-18, TNF-?, MIF, IL-8, MCP-1, MCP-4, MIP-3?, MIP-3?, Eotaxin, soluble IL-6 receptor, E-selectin, and P-selectin were analyzed by ELISA or Multiplex Assays. Serum miRNA expression changes were analyzed by qPCR. Results: Cellular parameters were similar in the improved and non-improved cohort on admission. In patients with rapid clinical recovery absolute and relative leukocyte, neutrophil, and lymphocyte numbers normalized promptly overnight. In contrast, HMGB-1 serum levels did not differ between the two groups. Nine miRNA were found to be differentially expressed between improved and non-improved patients. Conclusions: SIIA are detectable on admission of acute stroke patients. While it was assumed that post-stroke immunosuppression is rapidly reversed with improvement this is the first data set that shows that improvement actually is associated with a rapid reversal of SIIA demonstrating that SIIA require a constant signal to persist. The observation that HMGB-1 serum concentrations were similar in improved and non-improved cohorts argues against a role for this pro-inflammatory mediator in the maintenance of SIIA. Serum miRNA observed to be regulated in stroke in other publications was counter regulated with improvement in our cohort.

Dataset Information

Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain.

Publications

Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain.

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