FTY720 als Sphingosin-1-Phosphat-Rezeptor (S1P-R) Agonist verbessert partiell die Mikrozirkulation des Pankreas nach Ischämie/Reperfusion

Abstract

Introduction: Apart from immunological rejection, ischemia/reperfusion injury (IRS) still remains a serious complication following pancreas transplantation. The present study was designed to investigate the influence of FTY720 on pancreatic IRS. FTY720, a sphingosine 1-phosphate (S1P) analog, acts as an immunosuppressant through trapping of T cells in secondary lymphoid tissues. FTY720 was also shown to prevent tumor growth and to inhibit vascular permeability probably through a VEGF- dependent pathway [1]. Material and methods: Male Sprague-Dawley-Rats were anaesthetized and randomly assigned to three experimental groups: (I) sham (n = 7), (II) 60 min ischemia by temporary occlusion of the pancreas-supplying arteries followed by 60 min of reperfusion (ischemia-control, I/R, n = 7), (III) 60 min I/R and FTY720-treatment (2 mg/kg BW p. o. FTY720 6 h before ischemia, n = 5). Quantification of the effective microvascular permeability (P) was achieved by digital dynamic intravital-epifluorescence- microscopy; functional capillary density (FCD) and leukocyte-endothelial-interaction (LEI) were measured using intravital video-epifluorescence-microscopy. Results: Sham compared with I/R [P (*10-7 cm/s) 0.052 ± 0.067 vs. 1.487 ± 0.281; FCD (cm/cm2) 360 ± 13 vs. 258 ± 12; LEI (cells/mm2) 147 ± 23 vs. 310 ± 39] demonstrates a significant degradation of microcirculation with increased permeability, decreased capillary perfusion and increased number of adherent leukocytes. Except leucocyte endothelium interaction [LEI 311 ± 103] I/R + FTY720 led to a significant improvement of substantially raised parameters [P 0.361 ± 0.355, FKD 331 ± 8]. Statistical significance p < 0.05, MEAN ± SD, ANOVA on ranks and Student-Newman-Keuls-test. Conclusion: In this study we were able to show for the first time that FTY720 exhibits a protective effect in a model of pancreatic I/R-injury. Compared with conventional immunosuppressants — such as mTOR inhibitors — FTY720 as a sphingosine 1-phosphate analog (S1P) functions over a completely new signal mechanism. Possibly the protective effect of FTY720 directly correlates with its plasma concentration. In which way FTY720 detailly improves pancreatic microcirculation in ischemia/reperfusion, has yet to be examined in further experiments.