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

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.
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.
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.
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.
AuthorsMathias Martin, Christina Mory, Andrea Prescher, Christian Wittekind, Martin Fiedler, Dirk Uhlmann
JournalJournal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract (J Gastrointest Surg) Vol. 14 Issue 3 Pg. 511-9 (Mar 2010) ISSN: 1873-4626 [Electronic] United States
PMID19937475 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Biomarkers
  • Cytokines
  • Receptors, Lysosphingolipid
  • Toll-Like Receptor 4
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Alanine Transaminase (analysis)
  • Animals
  • Aspartate Aminotransferases (analysis)
  • Biomarkers (blood)
  • CD4 Lymphocyte Count
  • Cytokines (analysis)
  • Disease Models, Animal
  • Female
  • Immunohistochemistry
  • Liver Circulation (drug effects, physiology)
  • Liver Diseases (immunology, pathology, prevention & control)
  • Microcirculation (drug effects, physiology)
  • Microscopy, Fluorescence
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Receptors, Lysosphingolipid (antagonists & inhibitors)
  • Reperfusion Injury (immunology, pathology, prevention & control)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sensitivity and Specificity
  • T-Lymphocyte Subsets (metabolism)
  • Toll-Like Receptor 4 (analysis)

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