Inflammatory profile in a canine model of hypothermic circulatory arrest

Abstract

Background: Hypothermic circulatory arrest (HCA) is a technique used for complex repair of the aorta, but it can be associated with neurologic morbidity. To better understand the molecular changes that underlie ischemic brain injury, we assessed gene expression and cytokine/chemokine polypeptide concentration in brain tissue and cerebrospinal fluid (CSF) of canines that underwent two hours of HCA.

Materials and methods: Adult male canines were cannulated peripherally for cardiopulmonary bypass, cooled to 18°C, and arrested for two hours. Animals were euthanized two, eight, or 24 hours post-HCA (n = 8 per group), and their brains were compared to brains from eight normal canines, using gene expression microarray analysis, cytokine assay, and histopathology.

Results: Two to eight hours after HCA, pro-inflammatory cytokine mRNAs increased markedly, and gene expression was enriched within signaling pathways related to neuroinflammation or ischemic injury. Concentrations of pro-inflammatory cytokine polypeptides IL-6, IL-8, IL-1β, and CCL2 were very low in normal canine brain, whereas anti-inflammatory IL-10 and TGF-β1 were expressed at moderate levels. Pro-inflammatory cytokine concentrations rose robustly in cerebral tissue and CSF after HCA. IL-6 and IL-8 peaked at eight hours and declined at 24 hours, while IL-1β and CCL2 remained elevated. Concentrations of anti-inflammatory IL-10 and TGF-β1 were maintained after HCA, with a significant increase in TGF-β1 at 24 hours.

Conclusions: These cytokines represent potential diagnostic markers for ischemic neurologic injury that could be used to assess neurologic injury in patients undergoing HCA. The cellular mechanisms underlying this pro-inflammatory, ischemic-induced injury represent potential targets for neuroprotection in the future.

Keywords: Anti-inflammatory cytokines; Biomarkers of neurologic injury; Hypothermic circulatory arrest; Ischemic brain injury; Neuroinflammation; Neurologic injury; Pro-inflammatory cytokines.