Cerebral ischemia initiates an immediate innate immune response in neonates during cardiac surgery

Abstract

BackgroundA robust inflammatory response occurs in the hours and days following cerebral ischemia. However, little is known about the immediate innate immune response in the first minutes after an ischemic insult in humans. We utilized the use of circulatory arrest during cardiac surgery to assess this.MethodsTwelve neonates diagnosed with an aortic arch obstruction underwent cardiac surgery with cardiopulmonary bypass and approximately 30 minutes of deep hypothermic circulatory arrest (DHCA, representing cerebral ischemia). Blood samples were drawn from the vena cava superior immediately after DHCA and at various other time points from preoperatively to 24 hours after surgery. The innate immune response was assessed by neutrophil and monocyte count and phenotype using FACS, and concentrations of cytokines IL-1β, IL-6, IL-8, IL-10, TNFα, sVCAM-1 and MCP-1 were assessed using multiplex immunoassay. Results were compared to a simultaneously drawn sample from the arterial cannula. Twelve other neonates were randomly allocated to undergo the same procedure but with continuous antegrade cerebral perfusion (ACP).ResultsImmediately after cerebral ischemia (DHCA), neutrophil and monocyte counts were higher in venous blood than arterial (P = 0.03 and P = 0.02 respectively). The phenotypes of these cells showed an activated state (both P <0.01). Most striking was the increase in the ‘non-classical’ monocyte subpopulations (CD16intermediate; arterial 6.6% vs. venous 14%; CD16+ 13% vs. 22%, both P <0.01). Also, higher IL-6 and lower sVCAM-1 concentrations were found in venous blood (both P = 0.03). In contrast, in the ACP group, all inflammatory parameters remained stable.ConclusionsIn neonates, approximately 30 minutes of cerebral ischemia during deep hypothermia elicits an immediate innate immune response, especially of the monocyte compartment. This phenomenon may hold important clues for the understanding of the inflammatory response to stroke and its potentially detrimental consequences.Trial registrationClinicalTrial.gov: NCT01032876

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

“…Emerging evidence has demonstrated that hypoxia-ischemia induces the inflammatory responses in the brain parenchyma and the peripheral immune system, which play a critical role in mediating secondary neuronal death (Algra et al , 2013; Wang et al , 2010). In the neonatal brain, an immediate innate immune response occurs within minutes after the HI insult.…”

Inflammatory responses in hypoxic ischemic encephalopathy

“…Within hours after an insult to the brain of an adult, cytokines are produced in large amounts, and leukocytes are activated and migrate into the injured brain 10,11,12,13,14 . In neonates, however, cerebral ischemia initiates an immediate innate immune response even minutes after the insult 15 . Age differences in the mechanisms of stroke, some of them very striking, stem from immaturity of the CNS, including differences in the cross-talk between excitotoxic, oxidative and inflammatory injury mechanisms, creating “windows of susceptibility” to hypoxic-ischemic injury during embryonic and early postnatal brain development 16 .…”

Early Upregulation of NLRP3 in the Brain of Neonatal Mice Exposed to Hypoxia-Ischemia: No Early Neuroprotective Effects of NLRP3 Deficiency

“…A robust inflammatory response follows shortly after hypoxia-ischemia (HI) [2] , potentially providing both neuroprotective and damaging effects [3][4][5] . Innate immune responses are activated within minutes after ischemia [6] , resulting in the release of inflammatory cytokines such as interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is the principal activator of IL-1β and IL-18 [7] .…”