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

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Abstract

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.

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Author Contribution

AP: performed research/study, analysed data, wrote the paper

AJ: performed research/study, analysed data, collected data

LD: performed research/study, analysed data, collected data

MI: performed research/study, analysed data, collected data

MK: performed research/study, analysed data, collected data

AL: designed research/study, manuscript revision

PA: designed research/study, performed research/study, manuscript revision

UB: designed research/study, performed research/study, analysed data, manuscript revision

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  1. Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany

    Antonio Pinto, Annika Jahn, Moritz Benjamin Immohr, Alexander Jenke, Laura Döhrn, Markus Kornfeld, Artur Lichtenberg, Payam Akhyari & Udo Boeken

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  1. Antonio Pinto
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Correspondence to Payam Akhyari.

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This work was supported by a grant from Novartis Pharma GmbH.

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Pinto, A., Jahn, A., Immohr, M.B. et al. Modulation of Immunologic Response by Preventive Everolimus Application in a Rat CPB Model. Inflammation 39, 1771–1782 (2016). https://doi.org/10.1007/s10753-016-0412-5

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