title: Inflammatory cytokine and chemokine profiles are associated with patient outcome and the hyperadrenergic state following acute brain injury.
abstract: BACKGROUND
  Traumatic brain injury (TBI) elicits intense sympathetic nervous system (SNS) activation with profuse catecholamine secretion. The resultant hyperadrenergic state is linked to immunomodulation both within the brain and systemically. Dysregulated inflammation post-TBI exacerbates secondary brain injury and contributes to unfavorable patient outcomes including death. The aim of this study was to characterize the early dynamic profile of circulating inflammatory cytokines/chemokines in patients admitted for moderate-to-severe TBI, to examine interrelationships between these mediators and catecholamines, as well as clinical indices of injury severity and neurological outcome.
  
  
  METHODS
  Blood was sampled from 166 isolated TBI patients (aged 45 ± 20.3 years; 74.7 % male) on admission, 6-, 12-, and 24-h post-injury and from healthy controls (N = 21). Plasma cytokine [interleukin (IL)-1β, -2, -4, -5, -10, -12p70, -13, tumor necrosis factor (TNF)-α, interferon (IFN)-γ] and chemokine [IL-8, eotaxin, eotaxin-3, IFN-γ-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, -4, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1β, thymus activation regulated chemokine (TARC)] concentrations were analyzed using high-sensitivity electrochemiluminescence multiplex immunoassays. Plasma catecholamines [epinephrine (Epi), norepinephrine (NE)] were measured by immunoassay. Neurological outcome at 6 months was assessed using the extended Glasgow outcome scale (GOSE) dichotomized as good (>4) or poor (≤4) outcomes.
  
  
  RESULTS
  Patients showed altered levels of IL-10 and all chemokines assayed relative to controls. Significant differences in a number of markers were evident between moderate and severe TBI cohorts. Elevated IL-8, IL-10, and TNF-α, as well as alterations in 8 of 9 chemokines, were associated with poor outcome at 6 months. Notably, a positive association was found between Epi and IL-1β, IL-10, Eotaxin, IL-8, and MCP-1. NE was positively associated with IL-1β, IL-10, TNF-α, eotaxin, IL-8, IP-10, and MCP-1.
  
  
  CONCLUSIONS
  Our results provide further evidence that exaggerated SNS activation acutely after isolated TBI in humans may contribute to harmful peripheral inflammatory cytokine/chemokine dysregulation. These findings are consistent with a potentially beneficial role for therapies aimed at modulating the inflammatory response and hyperadrenergic state acutely post-injury.
authors.affiliation: Defence Research & Development Canada, Toronto Research Centre, Toronto, ON, Canada. dibattista.alex@gmail.com.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada. dibattista.alex@gmail.com.
authors.forename: Alex P
authors.initials: AP
authors.lastname: Di Battista
authors.affiliation: Defence Research & Development Canada, Toronto Research Centre, Toronto, ON, Canada. shawn.rhind@drdc-rddc.gc.ca.|Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada. shawn.rhind@drdc-rddc.gc.ca.
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Rhind
authors.affiliation: Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada. michael.hutchison@utoronto.ca.|Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hopsital, Toronto, ON, Canada. michael.hutchison@utoronto.ca.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hutchison
authors.affiliation: Defence Research & Development Canada, Toronto Research Centre, Toronto, ON, Canada. shaji.hassan@utoronto.ca.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada. shaji.hassan@utoronto.ca.
authors.forename: Syed
authors.initials: S
authors.lastname: Hassan
authors.affiliation: Defence Research & Development Canada, Toronto Research Centre, Toronto, ON, Canada. maria.shiu@drdc-rddc.gc.ca.|Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada. maria.shiu@drdc-rddc.gc.ca.
authors.forename: Maria Y
authors.initials: MY
authors.lastname: Shiu
authors.affiliation: Division of Trauma & Critical Care, University of Southern California, Los Angeles, CA, USA. Kenji.Inaba@med.usc.edu.|LA County+ USC Medical Center, Los Angeles, CA, USA. Kenji.Inaba@med.usc.edu.
authors.forename: Kenji
authors.initials: K
authors.lastname: Inaba
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hopsital, Toronto, ON, Canada. Topolovec-VranicJ@smh.ca.
authors.forename: Jane
authors.initials: J
authors.lastname: Topolovec-Vranic
authors.affiliation: Institute for Healthcare Improvement (IHI) Fellow, Cambridge, MA, USA. capone@einstein.br.
authors.forename: Antonio Capone
authors.initials: AC
authors.lastname: Neto
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hopsital, Toronto, ON, Canada. RizoliS@smh.ca.|Department of Critical Care, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. RizoliS@smh.ca.|Department of Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. RizoliS@smh.ca.|Department of Surgery, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. RizoliS@smh.ca.
authors.forename: Sandro B
authors.initials: SB
authors.lastname: Rizoli
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON, Canada. bakera@smh.ca.|Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hopsital, Toronto, ON, Canada. bakera@smh.ca.|Department of Critical Care, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. bakera@smh.ca.|Department of Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. bakera@smh.ca.|Department of Surgery, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. bakera@smh.ca.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Baker
mesh_terms: D000308:Adrenocortical Hyperfunction / Q000097:blood* / Q000209:etiology*; D000328:Adult; D000368:Aged; D001930:Brain Injuries / Q000150:complications*; D002395:Catecholamines / Q000097:blood; D016207:Cytokines / Q000097:blood*; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D008297:Male; D008875:Middle Aged; D013223:Statistics as Topic; D013997:Time Factors; D015898:Tomography Scanners, X-Ray Computed
chemical_list: D002395:Catecholamines; D016207:Cytokines