PMID- 24882386
OWN - NLM
STAT- MEDLINE
DCOM- 20151013
LR  - 20211021
IS  - 2042-0226 (Electronic)
IS  - 1672-7681 (Print)
IS  - 1672-7681 (Linking)
VI  - 12
IP  - 1
DP  - 2015 Jan
TI  - Effect of everolimus on the immunomodulation of the human neutrophil inflammatory 
      response and activation.
PG  - 40-52
LID - 10.1038/cmi.2014.24 [doi]
AB  - The primary cause of mortality at 5 years following a cardiac transplantation is 
      the development of atherosclerosis, termed coronary allograft vasculopathy (CAV). 
      This pathology is characterized by diffused intimal hyperplasia and emanates from 
      coronary arterial injuries caused by immune inflammatory cells. Neutrophils play 
      an important role in this inflammatory process; however, their potential 
      participation in the pathogenesis of CAV is poorly understood. Despite their 
      essential contribution to the prevention of graft rejection, immunosuppressive 
      drugs could have detrimental effects owing to their pro-inflammatory activities. 
      Thus, we investigated the impact of different immunosuppressive drugs on the 
      inflammatory response of neutrophils isolated from the blood of healthy 
      volunteers. Under basal conditions, mammalian target of rapamycin (mTOR) 
      inhibitors (sirolimus and everolimus) had the most potent anti-inflammatory 
      effect, decreasing both IL-8 release ( approximately -80%) and vascular endothelial growth 
      factor (VEGF) release ( approximately -65%) and preserving the release of the anti-inflammatory 
      cytokine interleukin-1 receptor antagonist (IL-1RA). In TNF-alpha-treated 
      neutrophils, pre-incubation with everolimus provided the most potent effect, 
      simultaneously reducing the release of both VEGF and IL-8 while doubling the 
      release of IL-1RA. This latter effect of everolimus was maintained even when 
      administered in combination with other immunosuppressive drugs. Sirolimus and 
      everolimus decreased the tumor necrosis factor (TNF)-alpha-induced adhesion of 
      neutrophils to human endothelial cells and human extracellular matrix. This 
      effect was largely dependent on the ability of these compounds to alter 
      beta2-integrin/CD18 activation. Our results suggest a potential mechanism for the 
      beneficial effect of everolimus in the prevention of CAV in heart transplant 
      recipients.
FAU - Vitiello, Damien
AU  - Vitiello D
AD  - 1] Research Center, Montreal Heart Institute, Universite de Montreal, Montreal, 
      QC, Canada [2] Department of Pharmacology, Faculty of Medicine, Universite de 
      Montreal, Montreal, QC, Canada [3] Department of Medicine, Faculty of Medicine, 
      Universite de Montreal, Montreal, QC, Canada.
FAU - Neagoe, Paul-Eduard
AU  - Neagoe PE
AD  - 1] Research Center, Montreal Heart Institute, Universite de Montreal, Montreal, 
      QC, Canada [2] Department of Pharmacology, Faculty of Medicine, Universite de 
      Montreal, Montreal, QC, Canada.
FAU - Sirois, Martin G
AU  - Sirois MG
AD  - 1] Research Center, Montreal Heart Institute, Universite de Montreal, Montreal, 
      QC, Canada [2] Department of Pharmacology, Faculty of Medicine, Universite de 
      Montreal, Montreal, QC, Canada.
FAU - White, Michel
AU  - White M
AD  - 1] Research Center, Montreal Heart Institute, Universite de Montreal, Montreal, 
      QC, Canada [2] Department of Medicine, Faculty of Medicine, Universite de 
      Montreal, Montreal, QC, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140602
PL  - China
TA  - Cell Mol Immunol
JT  - Cellular & molecular immunology
JID - 101242872
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (CD18 Antigens)
RN  - 0 (IL1RN protein, human)
RN  - 0 (Interleukin 1 Receptor Antagonist Protein)
RN  - 0 (Interleukin-8)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 9HW64Q8G6G (Everolimus)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Anti-Inflammatory Agents/*therapeutic use
MH  - CD18 Antigens/metabolism
MH  - Cell Adhesion/drug effects
MH  - Cells, Cultured
MH  - Coronary Vessels/*immunology
MH  - Drug Therapy, Combination
MH  - Everolimus
MH  - Female
MH  - *Heart Transplantation
MH  - Humans
MH  - Immunomodulation
MH  - Inflammation/*immunology
MH  - Interleukin 1 Receptor Antagonist Protein/metabolism
MH  - Interleukin-8/metabolism
MH  - Male
MH  - Middle Aged
MH  - Myocardium/*pathology
MH  - Neovascularization, Physiologic/drug effects
MH  - Neutrophils/*drug effects/immunology
MH  - Sirolimus/*analogs & derivatives/therapeutic use
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - Young Adult
PMC - PMC4654366
EDAT- 2014/06/03 06:00
MHDA- 2015/10/16 06:00
PMCR- 2015/01/01
CRDT- 2014/06/03 06:00
PHST- 2014/01/21 00:00 [received]
PHST- 2014/02/20 00:00 [revised]
PHST- 2014/03/16 00:00 [accepted]
PHST- 2014/06/03 06:00 [entrez]
PHST- 2014/06/03 06:00 [pubmed]
PHST- 2015/10/16 06:00 [medline]
PHST- 2015/01/01 00:00 [pmc-release]
AID - cmi201424 [pii]
AID - 10.1038/cmi.2014.24 [doi]
PST - ppublish
SO  - Cell Mol Immunol. 2015 Jan;12(1):40-52. doi: 10.1038/cmi.2014.24. Epub 2014 Jun 
      2.