Arachidonate cascade, apoptosis, and vitamin E in peripheral blood mononuclear cells from hemodialysis patients.
BACKGROUND
Lipid peroxidation and oxidative stress are enhanced in peripheral blood mononuclear cells (PBMCs) from hemodialysis (HD) patients because of upregulation of the 5-lipoxygenase pathway of the arachidonate cascade. 5-Lipoxygenase activity is specifically inhibited by vitamin E both in vitro and in vivo regardless of its administration route.


METHODS
The effect of arachidonate cascade enzymes and vitamin E on oxidative stress and apoptosis was investigated in PBMCs from 16 maintenance HD patients treated for at least 6 months with cuprammonium rayon membranes in a two-step crossover study: after a 4-week treatment with vitamin E-coated cuprammonium rayon membranes and again after a 4-week treatment with oral vitamin E. Control PBMCs were obtained from 16 healthy volunteers.


RESULTS
Membrane lipoperoxidation, cellular luminescence, membrane fluidity, and leukotriene B(4) content were significantly greater in PBMCs from HD patients; lipoxygenase was upregulated, but prostaglandin H synthase (PHS) was not affected. Regardless of administration route, vitamin E partially controlled lipid peroxidation and oxidative stress through direct inhibition of 5-lipoxygenase. Cultured PBMCs from HD patients showed a significant increase in apoptotic cells compared with controls. Vitamin E markedly reduced cell luminescence, membrane fluidity, and apoptosis, whereas the PHS inhibitor indomethacin was ineffective. Similar results were obtained with control PBMCs induced to apoptosis by hydrogen peroxide.


CONCLUSIONS
Reported data suggest that the 5-lipoxygenase branch of the arachidonate cascade is only responsible for membrane peroxidation, oxidative stress, and apoptosis of PBMCs of HD patients, and administration of vitamin E may be helpful in the control of oxidative stress-related disease in these subjects.
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy. maccarrone@med.uniroma2.it
Mauro
M
Maccarrone
Simone
S
Manca-di-Villahermosa
Carlo
C
Meloni
Renato
R
Massoud
Alberto
A
Mascali
Riccardo
R
Guarina
Alessandro
A
Finazzi-Agrò
Massimo
M
Taccone-Gallucci
D017209:Apoptosis / Q000187:drug effects*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D002482:Cellulose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D018592:Cross-Over Studies; D004333:Drug Administration Routes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology*; D007975:Leukotriene B4 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008163:Luminescent Measurements; D008560:Membrane Fluidity / Q000187:drug effects; D008567:Membranes, Artificial; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D006435:Renal Dialysis / Q000379:methods*; D015854:Up-Regulation / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D008567:Membranes, Artificial; C066013:AM 160H; D014810:Vitamin E; D007975:Leukotriene B4; D016718:Arachidonic Acid; D002482:Cellulose; D001094:Arachidonate 5-Lipoxygenase