Influence of an Early Application of Mammalian Target of Rapamycin Inhibitors Everolimus and Sirolimus on Acute Vascular Inflammatory Responses After Ischemia-Reperfusion Injury.

OBJECTIVES

Ischemia-reperfusion injury is correlated with a substantial inflammatory response. Inflammation triggers the migration of cells through vessel endothelium and leads to serious tissue injury. Our hypothesis was that an early application of mammalian target of rapamycin inhibitors has an impact on human vessels after ischemia-reperfusion injury.

MATERIALS AND METHODS

After exposure to ischemia for 5 hours, human vessels (veins and arteries) from 20 patients were reperfused for 120 minutes in an in vitro bioreactor with heparinized human blood after oxygenation and warming to 37 °C. The vessels were treated with mammalian target of rapamycin inhibitor everolimus (5 ng/mL, n = 7) or sirolimus (10 ng/mL, n = 6). As a control group, untreated human vessels were reperfused (n = 7). During the reperfusion period, blood samples were collected continuously (after 0, 15, 30, 60, 120 minutes); vessel biopsies were performed at the end. Oxygen consumption was measured during reperfusion to determine vessel viability. Inflammatory markers (interleukin 6, tumor necrosis factor α, vascular endothelial growth factor) were analyzed in blood samples. To quantify vascular inflammation, we investigated the expression of CD11 and CD31.

RESULTS

Physiological oxygen consumption and pH values verified vessel viability. After reperfusion, interleukin 6 and vascular endothelial growth factor levels were significantly increased in the control group over time, whereas everolimus and sirolimus showed no significant differences. Furthermore, tumor necrosis factor α level increased significantly in the sirolimus group, whereas the everolimus and control groups showed constant values. A significant decrease of expression of CD11b and CD31 in both mammalian target of rapamycin inhibitor cohorts compared with control cohort was investigated.

CONCLUSIONS

Early use of mammalian target of rapamycin inhibitors may limit an inflammatory rise of interleukin 6 and vascular endothelial growth factor after ischemia-reperfusion injury and could be associated with a restriction in vascular cell transmigration.