Reduced liver injury and cytokine release after transplantation of preconditioned intestines.
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.
Oltean
Mihai
M
Institute for Clinical Sciences, Department of Surgery, University of Gothenburg, Göteborg, Sweden. mihai.oltean@wlab.gu.se
Zhu
Changlian
C
Mera
Simona
S
Pullerits
Rille
R
Mattsby-Baltzer
Inger
I
Mölne
Johan
J
Hallberg
Eva
E
Blomgren
Klas
K
Olausson
Michael
M
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
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