FTY720 for treatment of ischemia-reperfusion injury following complete renal ischemia; impact on long-term survival and T-lymphocyte tissue infiltration.
BACKGROUND
Organ dysfunction due to ischemia-reperfusion (I/R) injury is a common problem in transplant, liver, trauma, and heart surgery. I/R injury is mediated by upregulated expression of endothelial cell surface adhesion molecules and subsequent adhesion and activation of circulating leukocytes. The purpose of this study was to evaluate the effect of an intraoperative administration of FTY720 in an animal model with controlled bilateral warm kidney ischemia compared to steroids or placebo application.


METHODS
Male C57BL6/J mice (n = 72, weight 25 to 30 g) were exposed to 30 minutes of bilateral kidney ischemia and followed by a 48 hour observation period. FTY720 (1 mg/kg body weight [BW]), steroids (5 mg/kg BW), or saline solution were administered. In addition, a sham-operated control group was included. At the termination of the experiments, all surviving animals were humanely killed. The impact of the various drugs on overall animal survival, timing of death, peripheral T-cell count, and T-lymphocyte infiltration in the kidneys was determined.


RESULTS
Following bilateral kidney I/R injury, FTY720 was associated with a significant improved animal survival (85.7%) compared with steroids (50%) or controls (42.4%). FACS analysis showed significant T-lymphocyte depletion in peripheral blood in the FTY720 but not in the other groups. T-lymphocyte tissue concentration in liver and kidney tissue did not show statistically significant differences following FTY720, steroid, or saline treatment.


CONCLUSIONS
FTY720, when administered intraoperatively, improved survival significantly in mice submitted to bilateral kidney ischemia but did not have any significant impact on the parenchymal T-lymphocyte infiltration in the ischemic organ.
Kaudel
C P
CP
Department of General-, Visceral- and Transplant Surgery, Hannover Medical School, Hannover, Germany. kaudel.philipp@mh-hannover.de
Frink
M
M
Schmiddem
U
U
Probst
C
C
Bergmann
S
S
Krettek
C
C
Klempnauer
J
J
van Griensven
M
M
Winkler
M
M
D000818:Animals; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000627:therapeutic use*; D012079:Renal Circulation / Q000187:drug effects*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine