title: Cerebral and hepatic inflammatory response after neonatal hypoxia-ischemia in newborn rats.
abstract: BACKGROUND
  Neonatal encephalopathy induced by perinatal asphyxia is a serious condition associated with high mortality and morbidity. Inflammation after the insult is thought to contribute to brain injury. This inflammatory response to hypoxia-ischemia (HI) may not only occur in the brain but also in peripheral organs. The aim of the present study was to investigate the effect of neonatal HI on the inflammatory response in the liver in comparison to inflammation in the brain.
  
  
  METHODS
  HI was induced in P7 Wistar rats by unilateral carotid artery occlusion and hypoxia. Cytokine and chemokine mRNA levels were determined in the brain and liver by quantitative PCR. Polarization of brain macrophages to the M1/M2-like phenotype and infiltration of neutrophils were characterized by immunohistochemistry.
  
  
  RESULTS
  3 h after HI, an upregulation of the proinflammatory cytokines TNF-α and IL-1β and anti-inflammatory IL-10 was observed in the ipsilateral hemisphere of the brain compared to mRNA levels in sham-operated animals. Additionally, cerebral CINC-1 and MCP-1 mRNA expressions were increased. We also observed increased numbers of macrophages/microglia of the M1-like phenotype as well as a small increase in granulocyte influx in the ipsilateral hemisphere. Conversely, in the liver 3 h after HI, a downregulation of TNF-α, IL-1β, and MCP-1 and a trend towards an upregulation of IL-10 were observed compared to mRNA levels of sham-operated animals. However, hepatic CINC-1 expression was increased compared to levels in sham-operated animals. Following systemic hypoxia only, no significant changes in the expression of TNF-α, CINC-1 or MCP-1 were observed in the liver compared to sham-operated littermates, except for an upregulation in hepatic IL-1β expression 3 h after hypoxia. Twenty-four hours after insult, cerebral ipsilateral TNF-α, MCP-1 and CINC-1 mRNA expression was still increased, together with an increase in TGF-β expression. Moreover, an increase in macrophages/microglia of the M1-like phenotype was observed together with the appearance of macrophages/microglia of the M2-like phenotype around the cerebral lesion as well as an increase in granulocyte influx in comparison to 3 h after HI. In the liver, 24 h after HI, cytokine and chemokine responses were similar to mRNA levels in sham-operated animals except for a decrease in IL-10 and MCP-1.
  
  
  CONCLUSIONS
  We describe for the first time that brain damage following neonatal HI induces an early downregulation of the proinflammatory response in the liver. HI induces an early proinflammatory response in the brain with a concomitant increase in influx of neutrophils and polarization of macrophages/microglia to the M1-like phenotype starting at 3 h and increasing up to 24 h after HI. The inflammatory state of the brain changes after 24 h, with an increase in the anti-inflammatory cytokine TGF-β together with the appearance of macrophages/microglia of the M2-like phenotype. The downregulation of proinflammatory cytokines in the liver is not due to systemic hypoxia only, but is induced by the cerebral damage.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: H J C
authors.initials: HJ
authors.lastname: Bonestroo
authors.forename: C H A
authors.initials: CH
authors.lastname: Nijboer
authors.forename: C T J
authors.initials: CT
authors.lastname: van Velthoven
authors.forename: A
authors.initials: A
authors.lastname: Kavelaars
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: F
authors.initials: F
authors.lastname: van Bel
authors.forename: C J
authors.initials: CJ
authors.lastname: Heijnen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016207:Cytokines