Protective effects of early CD4(+) T cell reduction in hepatic ischemia/reperfusion injury.
OBJECTIVE
CD4(+) T cells contribute to disturbances of liver microcirculation after warm ischemia/reperfusion (I/R). The aim of this study was to investigate a possible protective role of FTY720 (Sphingosine-1 phosphate receptor agonist) in this setting.


METHODS
In an in vivo model (42 Wistar rats), ischemia of the left liver lobe was induced for 90 min under anesthesia with xylazine/ketanest. Sham-operated untreated ischemic and treatment group with FTY720 (1 mg/kg body weight intravenous) were investigated. The effect of FTY on I/R injury was assessed by in vivo microscopy 30-90 min after reperfusion (perfusion rate, vessel diameter, leukocyte-endothelial cell interactions, T cell infiltration), by measurement of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), reverse transcription-polymerase chain reaction (RT-PCR) of interleukin (IL)-2, IL-6, IL-10, TNF-alpha, toll-like receptor 4 (TLR-4), and by histological investigation.


RESULTS
After 30 min of reperfusion, the number of T cells in sinusoids was increased four-fold. In the FTY group, the number of T cells was reduced to an half of the number of the ischemia group. Likewise, the number of adherent leukocytes in sinusoids (150.8 +/- 10.9% of s.o.) was reduced in the treatment group (117.3 +/- 12.2%; p < 0.05 vs ischemia), leading to an improvement in perfusion rate in this group (85.0 +/- 4.6% of sham group) compared to nontreated animals (57.5 +/- 10.8%; p < 0.05). According to improved microcirculation, AST/ALT values and histological tissue damage were reduced in the therapy group. RT-PCR revealed an increased expression of IL-2, IL-6, and TLR-4 in the nontreated ischemic group. This expression was clearly reduced in the treatment group.


CONCLUSIONS
In conclusion, FTY720 ameliorates the microcirculatory, biochemical, and histological manifestations of hepatic I/R injury by preventing T cell infiltration. These results indicate that T cells are pivotal mediators in hepatic I/R and may have important implications early after liver transplantation and in warm ischemia.
Martin
Mathias
M
2nd Department of Surgery, Leipzig, Germany.
Mory
Christina
C
Prescher
Andrea
A
Wittekind
Christian
C
Fiedler
Martin
M
Uhlmann
Dirk
D
D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D001219:Aspartate Aminotransferases / Q000032:analysis; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008107:Liver Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D008856:Microscopy, Fluorescence; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000032:analysis
D015415:Biomarkers; D016207:Cytokines; D049349:Receptors, Lysosphingolipid; D051197:Toll-Like Receptor 4; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase