title: Inflammatory immune responses in a reproducible mouse brain death model.
abstract: BACKGROUND
  Brain death impairs donor organ quality and accelerates immune responses after transplantation. Detailed aspects of immune activation following brain death remain unclear. We have established a mouse model and investigated the immediate consequences of brain death and anesthesia on immune responses.
  
  
  METHODS
  C57JBl/6 mice (n=6/group) were anesthetized with isoflurane (ISF) or ketamine/xylazine (KX); subsequently, animals underwent brain death induction and were followed for 3h under continuous ventilation. Blood pressure was monitored continuously and animals were resuscitated with normal saline to achieve normotension. Immune activation in brain dead animals was analyzed by IFNγ-ELispot, MLR, and flow-cytometry. Sham-operated and naïve animals served as controls.
  
  
  RESULTS
  Blood pressure remained stable in both BD/KX and BD/ISF animals during the 3h observation time. Brain death was linked to systemic immune activation: IFNγ-expression of splenocytes and lymphocyte proliferation rates was significantly elevated subsequent to brain death (p<0.02, <0.01); T-cell activation markers CD28 and CD69 had increased in brain dead animals (p<0.03, <0.02). Isoflurane treatment in sham controls throughout the observation period (3.5h) revealed anesthesia associated IFNγ-expression and lymphocyte activation which were not observed when animals were treated with ketamine/xylazine (p<0.04, <0.009).
  
  
  CONCLUSIONS
  This study reports on a reproducible and hemodynamically stable brain death mouse model. Hemodynamic stability was not impacted through either isoflurane or ketamine/xylazine induction. Of clinical relevance, prolonged anesthesia with isoflurane had been linked to pro-inflammatory cytokine activation. Brain death caused systemic immune activation in organ donors.
authors.affiliation: Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Floerchinger
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yuan
authors.forename: Anke
authors.initials: A
authors.lastname: Jurisch
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Timsit
authors.forename: Xupeng
authors.initials: X
authors.lastname: Ge
authors.forename: Ying-Lung
authors.initials: YL
authors.lastname: Lee
authors.forename: Christof
authors.initials: C
authors.lastname: Schmid
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Tullius
mesh_terms: D000758:Anesthesia; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001926:Brain Death / Q000503:physiopathology*; D018106:CD28 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007530:Isoflurane; D007649:Ketamine / Q000494:pharmacology; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D014180:Transplantation; D014181:Transplantation Immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D007371:Interferon-gamma; D007530:Isoflurane; D007649:Ketamine; D037181:Lectins, C-Type; D000099192:CD69 Antigens