title: Early activation of the inflammatory response in the liver of brain-dead non-human primates.
abstract: BACKGROUND
  Donor brain death (BD) triggers a systemic inflammatory response that reduces organ quality and increases immunogenicity of the graft. We characterized the early innate immune response induced by BD in the liver and peripheral blood of hemodinamically stable non-human primates (NHP).
  
  
  METHODS
  Rhesus macaques were assigned to either brain death or control group. BD was induced by inflation of a subdurally placed catheter and confirmed clinically and by cerebral angiography. Animals were monitored for 6 h after BD and managed to maintain hemodynamic stability.
  
  
  RESULTS
  Cortisol, epinephrine, nor-epinephrine, and IL-6 levels were elevated immediately after BD induction. Neutrophils and monocytes significantly increased in circulation following BD induction, while dendritic cells were decreased at 6 h post-induction. Flow cytometry revealed increased expression of chemokine receptors CxCR1, CxCR2, CCR2, and CCR5 in peripheral blood leukocytes from NHP subjected to BD. Microarray analysis demonstrated a significant up-regulation of genes related to innate inflammatory responses, toll-like receptor signaling, stress pathways, and apoptosis/cell death in BD subjects. Conversely, pathways related to glucose, lipid, and protein metabolism were down-regulated. In addition, increased expression of SOCS3, S100A8/A9, ICAM-1, MHC class II, neutrophil accumulation, and oxidative stress markers (carboxy-methyl-lysine and hydroxynonenal) were detected by immunoblot and immunohistochemistry.
  
  
  CONCLUSIONS
  Activation of the innate immune response after BD in association with a down-regulation of genes associated with cell metabolism pathways in the liver. These findings may provide a potential explanation for the reduced post-transplant function of organs from brain dead donors. In addition, this work suggests potential novel targets to improve donor management strategies.
authors.affiliation: Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, Wisconsin 53792-3236, USA.
authors.forename: Juan Sebastian
authors.initials: JS
authors.lastname: Danobeitia
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Sperger
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Hanson
authors.forename: Elisa E
authors.initials: EE
authors.lastname: Park
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Chlebeck
authors.forename: Drew A
authors.initials: DA
authors.lastname: Roenneburg
authors.forename: Mallory L
authors.initials: ML
authors.lastname: Sears
authors.forename: Jolien X
authors.initials: JX
authors.lastname: Connor
authors.forename: Alice
authors.initials: A
authors.lastname: Schwarznau
authors.forename: Luis A
authors.initials: LA
authors.lastname: Fernandez
mesh_terms: D000818:Animals; D001926:Brain Death / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D004837:Epinephrine / Q000097:blood; D020869:Gene Expression Profiling; D006505:Hepatitis / Q000235:genetics / Q000276:immunology*; D006854:Hydrocortisone / Q000097:blood; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007728:Kupffer Cells / Q000276:immunology; D008099:Liver / Q000276:immunology*; D016031:Liver Transplantation; D008214:Lymphocytes / Q000276:immunology; D008253:Macaca mulatta; D009504:Neutrophils / Q000276:immunology; D009638:Norepinephrine / Q000097:blood; D014019:Tissue Donors; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine