title: Modulation of Immunologic Response by Preventive Everolimus Application in a Rat CPB Model.
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.
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Jahn
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany.
authors.forename: Moritz Benjamin
authors.initials: MB
authors.lastname: Immohr
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jenke
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Döhrn
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kornfeld
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany.
authors.forename: Artur
authors.initials: A
authors.lastname: Lichtenberg
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany. payam.akhyari@med.uni-duesseldorf.de.
authors.forename: Payam
authors.initials: P
authors.lastname: Akhyari
authors.affiliation: Department of Cardiovascular Surgery, Medical Faculty, Heinrich-Heine-University Medical School, Moorenstrasse 5, 40225, Duesseldorf, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Boeken
mesh_terms: D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D000068338:Everolimus / Q000008:administration & dosage / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D023421:Models, Animal; D011292:Premedication; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control; D018746:Systemic Inflammatory Response Syndrome / Q000517:prevention & control; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: cardiopulmonary bypass; cytokine; deep hypothermic cardiac arrest; everolimus; ischemia; reperfusion; systemic inflammatory syndrome