Short antioxidant treatment / premature destruction of RBC

2005-12-19 11:56:41 PM
These two articles seem to confirm increased oxidative stress leads to
increased hemolysis .. and again .. gives credence to the lack of
vitamin E hypothesis ..
Lack of vitamin E is KNOWN to increase hemolysis .. leading to ..
'anemia' ..
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Role of iron in inducing oxidative stress in thalassemia: can it be
prevented by inhibition of absorption and by antioxidants?
Ann N Y Acad Sci. 2005 Nov; 1054: 118-23
Rachmilewitz EA, Weizer-Stern O, Adamsky K, Amariglio N, Rechavi G,
Breda L,
Rivella S, Cabantchik ZI
The pathophysiology of thalassemia is, to a certain extent, associated
with
the generation of labile iron in the pathological red blood cell (RBC).
The
appearance of such forms of iron at the inner and outer cell surfaces
exposes the cell to conditions whereby the labile metal promotes the
formation of reactive oxygen species (ROS) leading to cumulative cell
damage. Another source of iron accumulation results from increased
absorption due to decreased expression of hepcidin. The presence of
labile
plasma iron (LPI) was carried out using fluorescent probes in the FACS.
RNA
expression of hepcidin was measured in two models of thalassemic mice.
Hepcidin expression was also measured in human hapatoma HepG2 cells
following incubation with thalassemic sera. LPI was identified and
could be
quantitatively measured and correlated with other parameters of iron
overload. Hepcidin expression was downregulated in the livers of
thalassemic
mice, in major more than in intermedia. Thalassemic sera down regulated
hepcidin expression in HepG2 liver cells. A possible way to decrease
iron
absorption could be by modulating hepcidin expression
pharmacologically, by
gene therapy or by its administration. Treatment with combination of
antioxidants such as N-acetylcysteine for proteins and vitamin E for
lipids
in addition to iron chelators could neutralize the deleterious effects
of
ROS and monitored by quantitation of LPI.
Read more <">www.hubmed.org/display.cgi>
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Blood (ASH Annual Meeting Abstracts) 2005 106: Abstract 3643
?2005 American Society of Hematology
Oxidative Stress of RBC in a Murine Model of Beta-Thalassemia Can Be
Reversed by Treatment with Antioxidants.
Eitan Fibach, PhD1, Johnny Amer, M.Sc.1,*, Eliezer Rachmilewitz, M.D2,
Ella Guy, M.Sc.3,* and Stefano Rivella, Ph.D3
1 Hematology, Hadassah - Hebrew University Medical Center, Jerusalem,
Israel; 2 Hematology, Wolfson Medical Center, Holon, Israel and 3
Pediatric Hematology-Oncology, Weill Medical College of Cornell
University, New York, NY, USA.
Abstract
Oxidative stress is a prominent contributor to the premature
destruction of RBC as well as anemia in thalassemia and sickle cell
anemia. The oxidative status within RBC is maintained by the balance
between oxidative systems, such as Reactive Oxygen Species (ROS), and
antioxidative systems, such as reduced glutathione (GSH). Using flow
cytometric methods, we previously showed that RBC obtained from
patients with thalassemia (Amer et al. Eur J Haematol
70:84,2003[Medline]; Cytometry 60:73,2004[Medline]) or sickle cell
anemia (Amer et al. Blood, 104:972a,2004) exhibit oxidative stress. In
the present study, we assessed the extent of RBC oxidative stress and
the effects of antioxidant administration, using the thalassemic mouse
model Th3/+. This model closely mimics the phenotype observed in
patients affected by beta-thalassemia intermedia, such as low
hemoglobin levels (7 to 9 gr/dL), splenomegaly and iron overload. In
addition, the mature RBC have a shorter life-span and are characterized
by anisocytosis, poikilocytosis and hypochromatism.
RBC were derived from normal and thalassemic mice before and 4 hours
after i.p. injection of the antioxidants N-acetyl cysteine (NAC),
vitamin C (Vit. C) or tocotrinol - a mixture of vitamin E derivatives,
at a dose of 150 mg/kg. Intracellular ROS was determined in
dichlorofluorescin diacetate-stained RBC following stimulation with 2
mM H2O2; GSH content was assessed in RBC stained with mercury orange.
Cells were analyzed by flow cytometry: RBC were gated according to size
(forward light scatter) and granularity (side light scatter), their
fluorescence was measured and the Mean Fluorescence Channel (MFC) was
calculated. Fig. 1 shows the average MFC of ROS and GSH of normal and
thalassemic mice treated or not treated with anti-oxidants (N=6 in each
group).
The results show a significantly higher (2.6-fold) production of ROS
and lower (three-fold) levels of GSH in RBC from the thalassemic mice
versus those in RBC from normal mice. Administration of antioxidants
decreased the ROS of normal and thalassemic RBC by 1.4-fold and
2.6-fold, respectively, whereas GSH levels were significantly increased
both in the normal (2.7 fold) and in the thalassemic (9.4-fold) RBC.
The results show that the RBC of thalassemic mice are under oxidative
stress that could be ameliorated by a short antioxidant treatment.
Hence, this mouse model recapitulates the oxidative stress found in
thalassemic patients and can serve as a model for studying the effects
of antioxidant therapy. The flow cytometry methodology used is helpful
in following up the results of the treatment and in evaluating its
efficacy in reducing oxidative stress.
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Copyright ?2005 by the American Society of Hematology.
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