title: Reduced liver injury and cytokine release after transplantation of preconditioned intestines.
abstract: BACKGROUND
  The postischemic intestine liberates pro-inflammatory mediators (cytokines, lipopolysaccharide [LPS], free radicals) proportional with the local injury that may trigger a systemic inflammatory response and multi-system organ failure. Previously, intestines from donors receiving Tacrolimus revealed improved morphology and abrogated nuclear factor kappa B (NF-kappaB) activation. Because of its pivotal role in inflammation, we investigated if NF-kappaB intragraft inhibition influences the posttransplant inflammatory response and remote organ injury.
  
  
  METHODS
  Donor Sprague Dawley rats received tacrolimus (0.3 mg/kg) or saline i.v. 6 h before graft harvest. The intestines were preserved for 3 h and then transplanted heterotopically. Hepatic microcirculation was assessed at 20 min, 6 h, 12 h, or 24 h post-reperfusion (postR) using laser-Doppler flowmetry (n = 10/group). Blood pressure measurements and liver sampling were performed at 6, 12, or 24 h postR. Blood samples were obtained at 1, 3, 6, 12, and 24 h postR. Hepatic intercellular adhesion molecule 1 (ICAM-1) expression, caspase-3 and -9 activity, and circulating tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and LPS were studied.
  
  
  RESULTS
  Pretreated graft (PG) recipients had superior cardiovascular parameters at 6 and 12 h postR, while liver perfusion was similar between groups at all time points. Recipients of PG had lower transaminase levels and ICAM-1 liver expression. Liver caspase 3 and 9 activity were similar at 6 and 12 h but increased at 24 h in both groups. At every time point, circulating tumor necrosis factor alph, IL-1beta, and IL-6 were lower in animals receiving PG. LPS was found increased only at the last time point.
  
  
  CONCLUSIONS
  Transplantation of tacrolimus-pretreated intestines triggered a milder inflammatory response and decreased liver injury early posttransplantation compared with untreated grafts. Cytokines, but not neutrophils, hypoperfusion, or LPS may underlie the dysfunction.
authors.affiliation: Institute for Clinical Sciences, Department of Surgery, University of Gothenburg, Göteborg, Sweden. mihai.oltean@wlab.gu.se
authors.forename: Mihai
authors.initials: M
authors.lastname: Oltean
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
authors.forename: Simona
authors.initials: S
authors.lastname: Mera
authors.forename: Rille
authors.initials: R
authors.lastname: Pullerits
authors.forename: Inger
authors.initials: I
authors.lastname: Mattsby-Baltzer
authors.forename: Johan
authors.initials: J
authors.lastname: Mölne
authors.forename: Eva
authors.initials: E
authors.lastname: Hallberg
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
authors.forename: Michael
authors.initials: M
authors.lastname: Olausson
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007422:Intestines / Q000637:transplantation*; D019194:Ischemic Preconditioning / Q000379:methods*; D008070:Lipopolysaccharides / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000293:injuries*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D016559:Tacrolimus / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3; D053453:Caspase 9; D016559:Tacrolimus