Cytokine and chemokine responses to injury and treatment in a nonhuman primate model of hypoxic-ischemic encephalopathy treated with hypothermia and erythropoietin

Abstract

Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine Macaca nemestrina were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h–6h, and significantly lower MCP-4 and MDC at 24 h–72h, respectively. IL-12p40 was lower at 24 h–72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.

The intra‐arterial selective cooling infusion system: A mathematical temperature analysis and in vitro experiments for acute ischemic stroke therapy

“…However, in some of the large animal and non‐human primate studies, the reduction of infarct size and improved functional outcomes induced by selective brain cooling were not statistically different from their control groups, which may ascribe to the small sample size. Therefore, a larger number of subjects might be required to demonstrate the efficacy of this technique 50,51 …”

“…Therefore, a larger number of subjects might be required to demonstrate the efficacy of this technique. 50 , 51 …”

“…Therefore, a larger number of subjects might be required to demonstrate the efficacy of this technique. 50,51 The time to target temperature and the brain temperature from the in vivo and in vitro study is compared in Table 3. The calculation results from the numerical theoretical model in this manuscript were compatible with the brain temperature estimation of rat, monkey, and human during IA-SCAI.…”

RAGE-mediated T cell metabolic reprogramming shapes T cell inflammatory response after stroke

“…Cerebral ischemic stroke elicits profound changes in the peripheral immune system, including the early immune activation and subsequent immune suppression. 28–31 Our previous study found that peripheral CD4 + T cells underwent metabolic reprogramming with increased glycolysis and fatty acid synthesis after stroke. 17 However, the mechanisms underlying the metabolic reprogramming the CD4 + T cells after stroke remains largely unknown.…”

Early evolution of glial morphology and inflammatory cytokines following hypoxic-ischemic injury in the newborn piglet brain

“…Most of the research has studied human serum cytokine levels at one or two time points, generally between 24 and 72 h. Animal studies allow for frequent serial sampling at multiple timepoints. Woods et al 7 in the nonhuman primate model measured plasma cytokines, chemokines, and growth factors at 3, 6, 24, 72, and 96 h after umbilical cord occlusion, treated with hypothermia therapy (HTH) and erythropoietin and observed complex alterations in circulating chemokines based on severity of injury and response to therapy with hypothermia and erythropoietin. Rocha-Ferreira et al, reported alterations in serum levels of a number of cytokines following hypoxic-ischemic (HI) injury and HTH in a neonatal pig model 8 .…”