Modulation of Immunologic Response by Preventive Everolimus Application in a Rat CPB Model

Everolimus (EVL) is widely used in solid organ transplantation. It is known to have antiproliferative and immunosuppressive abilities via inhibition of the mTOR pathway. Preventive EVL administration may lower inflammation induced by cardiopulmonary bypass (CPB) and reduce systemic inflammatory response syndrome (SIRS). After oral loading with EVL 2.5 mg/kg/day (n = 11) or placebo (n = 11) for seven consecutive days, male Wistar rats (400-500 g) were connected to a miniaturised heart-lung-machine performing a deep hypothermic circulatory arrest protocol. White blood cells (WBC) were significantly reduced in EVL-pretreated animals before start of CPB with a preserved reduction by trend at all other time points. Ischemia/reperfusion led to decreased glucose levels. Application of EVL significantly increased glucose levels after reperfusion. In addition, potassium levels were significantly lower in EVL-treated animals at the end of reperfusion. Immunoblotting revealed increased S6 levels after CPB. EVL decreased phosphorylation of S6 in the heart and kidney, which indicates an inhibition of mTOR pathway. Moreover, EVL significantly modified phosphorylation of AKT, while decreasing IL2, IL6, RANTES, and TNFα (n = 6). Preventive application of EVL may modulate inflammation by inhibition of mammalian target of rapamycin (mTOR) pathway and reduction of proinflammatory cytokines. This may be beneficial to evade SIRS-related morbidities after CPB.