Protective effects of early CD4(+) T cell reduction in hepatic ischemia/reperfusion injury.

AIM

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.

MATERIAL AND 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.

CONCLUSION

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.