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Nitric oxide metabolism is altered during the acute chest syndrome of sickle cell disease. In the presence of oxygen and oxygen-related molecules, nitric oxide can preferentially form the powerful oxidants nitrite, nitrate, and peroxynitrite. We hypothesized that increased oxidative stress may contribute to the pathogenesis of acute chest syndrome and measured F2 isoprostanes, a nonenzymatically generated molecule resulting from free radical catalyzed lipid peroxidation in patients with sickle cell disease in various stages of disease. Plasma samples were obtained from nineteen patients with sickle cell disease during acute chest syndrome (pre- and postexchange transfusion), vasoocclusive crisis, and/or at baseline; 12 normal volunteers served as controls. F2 isoprostanes were measured by gas chromatography/mass spectrophotometry. There was a 9-fold increase in F2 isoprostanes in patients with acute chest syndrome as compared with normal volunteers. There was approximately a 50-60% decline in isoprostanes postexchange transfusion to a level similar to that of patients with sickle cell disease at baseline. There was no difference in isoprostanes between vasoocclusive crisis and patients with sickle cell disease at baseline. Increased oxidative stress, measured by generation of F2 isoprostanes, occurs during acute chest syndrome and may have an important role in the pathogenesis of this disease process.
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Keywords: hemoglobin; lung disease; reactive oxygen species; nitric oxide
Acute chest sydrome (ACS) is a common complication of sickle
cell diseawe (SCD), occurring in approximately 40% of patients; moreover recurrent episodes occur in up to 80% of those
who have had a prior episode (1). Despite the frequence of
ACS, little is know about the mechanisms responsible for its
development. However, recent studies suggest that abnormalities in endothelial cell (EC) nitric oxide (NO) production and
metabolism as well as oxidant status may play a role in its development (5). Although NO can have beneficial actions such
as vasodilation and inhibition of platelet aggregation, in the
presence of oxygen and oxygen-related compounds, it preferentially and rapidly forms the powerful oxidants nitrite (NO2),
nitrate (NO3), and peroxynitrite (ONOO
) (6). Schacter
and coworkers and Gryglewski and coworkers have demonstrated decreased levels of superoxide dismutase (SOD) and
catalase in red blood cells (RBCs) from patients with stable SCD suggesting that there is increased availability of superoxide (O2) and hydrogen peroxide (H2O2) in these patients
(9). Furthermore, we have demonstrated that exposure of
EC to plasma from patients with ACS results in reduction of
the antioxidant glutathione reductase systems in vitro and favors metabolism from NO to ONOO (5). Together, these
data suggest that alterations in the redox state exist at baseline
in patients with SCD and that the pathophysiology of ACS
may, in part, relate to increased oxidative stress. Whether these
findings are relevant in vivo is not yet clear, in part because of
a lack of a sensitive and specific assay for oxidative stress (12).
Recent studies suggest that F2 isoprostanes, compounds formed
from peroxidation of lipid-bound arachidonic acid by a noncyclooxygenase-mediated pathway, are reliable markers of oxidative stress and can be readily measured in numerous bodily fluids (13). Levels of this compound are elevated in experimental models of lipid peroxidation as well as in clinical disease states and other conditions characterized by vascular
pathology such as cigarette smoking, hypercholesterolemia,
atherosclerosis, and diabetes mellitus (14, 17). Moreover,
the most biologically active of these compounds, 8-epi-PGF2
,
may also play a role in pulmonary and renal vasoconstriction
(13). Based on these findings and the fact that ONOO has
been implicated in peroxidation of the lipid membrane (22), we hypothesized that F2 isoprostane production would increase during ACS. In the current study, we examined the
production of F2 isoprostanes in patients with SCD at various
stages of their disease process.
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Patient Selection
Nineteen patients with sickle cell disease (hemoglobin SS or SC disease) and 12 age- and sex-matched healthy volunteers were studied at Boston Medical Center between 1997 and 1999. Plasma samples were obtained from patients with sickle cell disease at baseline (routine outpatient visits), during ACS, and/or during vasoocclusive crisis (VOC). Samples were obtained at more than one timepoint in three patients. ACS was defined as the presence of shortness of breath, hypoxemia, and infiltrates on chest radiographs, with or without bacteriological evidence of pneumonia (3). VOC was defined as the presence of signs or symptoms of peripheral vasoocclusion without the presence of respiratory pathology. Baseline samples were obtained at least 2 wk postcrisis. Samples were obtained from patients with ACS upon arrival in the Medical Intensive Care Unit (preexchange) and postexchange transfusion of an average of four units of packed RBCs. Informed consent was obtained from each patient in concordance with the Institutional Review Board of Boston Medical Center. Exclusion criteria consisted of entities associated with elevated isoprostanes such as daily cigarette or ethanol use, age > 55 yr, diabetes mellitus, renal dysfunction (creatinine > 1.5), serum cholesterol > 220, or symptomatic coronary artery disease.
Plasma Preparation
Peripheral blood samples were obtained in heparinized syringes and
stored on ice for less than 12 h. Samples were centrifuged at 2000 × g
for 15 min. Platelet poor plasma was obtained by centrifuging the supernatant at 20,000 × g for 20 min (5, 23). Platelet poor plasma was
used for determination of isoprostanes as this was the component of
serum that resulted in NO production when incubated with ECs (5).
Samples were stored at 
70° C until measurement of isoprostanes.
Measurement of F2 Isoprostanes
F2 isoprostanes in plasma were quantified after purification by gas
chromatography/negative-ion chemical ionization mass spectroscopy (GC/MS) by modification of our previously published methods (14, 15, 24). Briefly, 0.5 ng of tetradeuterated 8-iso-PGF2 standard was
added to 1 ml of plasma and allowed to equilibrate. Following acidification to pH 3 with 1 N HCl, lipids were purified with reverse-phase
and straight-phase silica cartridges (Waters Associates, Milford, MA).
After concentration, samples were purified by thin-layer chromatography (TLC) on LK6D plates with a mobile phase of chloroform/
methanol/acetic acid/water (86:14:1:0.8, vol/vol/vol/vol). Samples were
eluted from the appropriate silica segments, concentrated, and converted to the corresponding pentafluorobenzyl ester by addition of
40 µl 10% pentafluorobenzyl bromide in acetonitrile and 20 µl 10%
N,N-diisopropylethylamine. Samples were then purified by TLC using
a mobile phase of chloroform/ethanol (93:7, vol/vol). After concentration, samples were converted to the trimethylsilyl ether derivative by
addition of 20 µl N,O-bis (trimethylsilyl)trifluoroacetamide (BSTFA)
and 20 µl dimethylformamide (DMF) and incubation at 40° C for 20 min.
The sample was then dried and redissolved in undecane in preparation for GC/MS using a Varian-Vista instrument (Sunnyvale, CA) and
a Nermag R1010C mass spectrometer (Fairfield, NJ). Endogenously generated isoprostane, in ng/ml, was quantified by comparison of
peak areas obtained by monitoring selected ions m/z 569 (endogenous isoprostane) and 573 (tetradeuterated internal standard).
Statistical Analysis
Patient characteristics and laboratory data are presented as means ± SD. Mass spectrophotometry data are presented as medians with the 25th-75th percentile range. Comparison within patient groups was made nonparametrically using the Wilcoxon rank sum test. Differences were considered significant if p < 0.05.
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Patient Characteristics
Plasma samples were obtained from 19 patients with SCD and 12 normal volunteers. Samples from three patients were obtained during different disease states. All patients with ACS had pre- and postexchange transfusion samples obtained. There was no significant difference in age and sex between the two groups. Although there was a significant racial difference between the patients with SCD and normal volunteers, no significant difference in the level of isoprostanes was noted between African American and white normal volunteers (data not shown). Among the different SCD patient groups (ACS, VOC, and SCD baseline), there was no significant difference in the frequency of prior pulmonary or nonpulmonary vasoocclusive events, white blood cell (WBC) count, hemoglobin, hematocrit, or reticulocyte count. Baseline laboratory values were not obtained in normal volunteers. There was a trend toward an increase in platelet count in patients with ACS compared with patients with VOC and patients with SCD at baseline (541.83 ± 218.5 versus 389 ± 175.91 versus 336.8 ± 153, respectively [ACS versus patients with SCD at baseline, p = 0.11]). Oxygen saturation, measured by pulse oximetry at the time of admission, differed significantly between ACS and VOC patients (89.9 ± 1.5 versus 98.0 ± 2.0), (p = 0.0002) (Tables 1 and 2).
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Measurement of F2 Isoprostanes by Mass Spectrophotometry
By GC/MS, there was approximately a 9-fold increase in the plasma level of F2 isoprostanes in patients with ACS (preexchange transfusion) as compared with normal volunteers (0.61 [range 0.09-1.03] ng/ml versus 0.07 [range 0.05-0.11] ng/ml, p = 0.02) (Figure 1). Compared with patients with SCD at baseline, an approximately 6-fold increase was observed in patients with ACS (0.61 [range 0.09-1.03] ng/ml versus 0.11 [range 0.05-0.42] ng/ml, p = 0.34). Levels of isoprostanes decreased by approximately 85% after exchange transfusion (0.61 [range 0.09-1.03] ng/ml versus 0.093 ng/ml [range 0.081-1.34], p = 0.39) to values similar to those observed at baseline. Interestingly, in this patient group, there was no significant difference between levels of isoprostanes measured in patients with a non-pulmonary vasoocclusive crisis (0.15 [range 0.10-0.16] ng/ml) and either patients with SCD at baseline (0.11 [range 0.05-0.92] ng/ml, p = 0.34) or normal volunteers (0.07 [range 0.05-0.11] ng/ml, p = 0.5). Although the difference between these groups was not significant due to individual variance (Figure 2), the elevated median reflective of several very high values in patients with SCD at baseline suggests that some patients with SCD have increased levels of oxidative stress even when clinically stable.
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Acute chest syndrome is a common complication of SCD; recurrent episodes are the primary risk factor for the development of chronic sickle cell lung disease characterized by
pulmonary hypertension, cor pulmonale, and death (1, 2). Although the etiology of ACS is likely multifactorial, the hallmark pathological event is vasoocclusion and resultant altered
vascular flow, the precise mechanism of which is unclear. Although the historical literature supports a primary role for the
RBC, there is an increasing body of evidence that the endothelium, through its interactions with the sickled RBC, may
have an instrumental role in this process, in part via release of
vasoactive mediators such as endothelin-1 and NO (5, 23, 25-
27). NO may play a beneficial role in this disorder by both
producing vasodilation and inhibition of platelet aggregation
and migration (6); however, in the presence of O2, it rapidly
forms ONOO (6). This may be of relevance in ACS because
of evidence of alterations in antioxidant defense systems in SCD
as well as elevated levels of O2 and H2O2 (5, 9, 28) suggesting that NO that is produced during this disease state is shunted
preferentially toward the formation of toxic metabolites such as
ONOO (5). During ACS, the sources of free radical generation are likely multiple. In vitro, we have demonstrated endothelial production of ONOO (5) and have hypothesized that isoprostanes are formed via the reactions of ·NO2 and ·OH with
arachidonic acid. In vivo, increased levels of oxidants can occur
through several mechanisms. Hemoglobin (Hb) S generates O2
to a greater extent than Hb A (30) and deficiencies in SOD activity in sickle RBCs at baseline (10) suggest that there is an inability to metabolize O2 to H2O2 and H2O.
Once formed, ONOO is the most powerful oxidant produced endogenously within the body. It has been implicated in
atherosclerosis, ischemia-reperfusion injury, and carcinogenesis (7). At physiological pH and temperature, it exists in equilibrium with peroxynitrous acid (ONOOH), which spontaneously decomposes to ·NO2 and ·OH; each of these molecules
can initiate lipid peroxidation via H+ abstraction of polyunsaturated fatty acids (8, 22, 29).
Although our previous in vitro studies suggest that
ONOO formation occurs during ACS due to an increase in
NO production in an oxidative milieu, demonstration of such
a milieu in vivo is essential to the potential biological relevance of this observation. As a reflection of the oxidative state
of patients with SCD, we chose to examine F2 isoprostanes,
chemically stable compounds formed via a noncyclooxygenase-mediated mechanism from arachidonic acid. These compounds are formed in situ on the plasma membrane and then
released into the bloodstream via the actions of yet unknown
phospholipases (15, 29). They are formed when free radicals
attack unsaturated lipids and are considered reliable markers
of increased oxidative stress as they are not increased in the
setting of cell death (14). Moreover, they have been implicated in the alteration of fluidity and integrity of endothelial cellular membranes associated with cellular dysfunction and
apoptosis (15). Once released into the plasma, isoprostanes
may interact with the vascular thromboxane A2/prostaglandin
H2 receptor to contribute to vasoconstriction (17). Although
this was initially thought to be the primary receptor target for
isoprostanes, there is speculation that other as yet unidentified
receptors also play a role in the vasoconstrictive process. During
ACS, isoprostanes may contribute directly to the development
of pulmonary vasoocclusion via this mechanism. Additionally,
isoprostanes may inhibit the physiological antiplatelet activity
of NO; as such, generation of these molecules could contribute to the increased platelet adherence to the endothelium
(17, 31), observed during ACS (28).
In the current study, we have demonstrated a 9-fold increase
in the plasma level of F2 isoprostanes in patients with ACS compared with normal volunteers. This increase occurs at the onset
of crisis and correlates with the patient's clinical status as there
is a decline of approximately 50-85% postexchange transfusion. Exchange transfusion, the removal of units of blood from
patients with SCD and replacement with that of normal patients, is the only treatment for ACS with documented beneficial effects on morbidity and mortality (32). Part of the efficacy of exchange transfusion may be via a decrease in the level
of reactive oxygen species in the plasma of patients with ACS.
The mechanism by which this occurs is not clear but may involve the removal of RBCs and WBCs from patients with
SCD, both of which have the ability to generate oxygen radicals (10, 11, 28). As alluded to in our previous work, as yet unidentified factors, present in the plasma of patients with ACS,
appear responsible for generation of NO from the vascular endothelium (5). Replacement of sickle RBCs with normal
RBCs apparently decreases activation of the endothelium
since NO production decreases to the same level observed in
plasma from patients with SCD at baseline (5). This decline in
NO production as well as a decrease in the level of reactive
oxygen species results in a decrease in ONOO production
and may be responsible for lower levels of isoprostanes that
we observed in the current study. The correlation between the
level of isoprostanes and the patients' clinical condition suggests
that increased oxidative stress plays an important role in the
pathogenesis of ACS and correction of the oxidative milieu is
essential for treatment of this disorder.
Our findings could suggest a potential therapeutic benefit of
administration of exogenous antioxidants for the prevention of
ACS in SCD. Unfortunately, despite reports of decreases in levels of cellular antioxidants in most studies, supplementation has not been beneficial. The studies evaluating their use have been less than convincing. The best studied of the exogenous
cellular antioxidants, 
-tocopherol (vitamin E), ascorbic acid
(vitamin C), and 
-carotene (vitamin A), has been vitamin E. Patients with SCD have an approximate 30% reduction in vitamin E levels (30, 33); furthermore, there is an inverse correlation between vitamin E levels and the percentage of irreversibly
sickled RBCs (34). Although it appears that vitamin E depletion may play a role in the development of vasoocclusion, the
effect of vitamin E supplementation in patients with SCD is unclear. In two small prospective studies, there was a decrease in
the number of irreversibly sickled cells, but this did not correlate with a reduction in the number or severity of VOC (35, 36).
Although patients with SCD have an approximate 40% reduction in plasma carotene levels, there are no studies of vitamin A
supplementation in patients with SCD. Measurement of ascorbic acid levels in SCD has produced conflicting results; several
studies have demonstrated reduced levels in the plasma and
WBCs of patients with SCD but others have found no significant difference (37). This disparity may reflect differences in
the populations studied but makes it less likely that vitamin C
represents an important antioxidant in this population. To date,
there have been no clinical trials evaluating the efficacy of vitamin C supplementation in the SCD population.
Of interest is the difference in the level of isoprostanes we observed between ACS and nonpulmonary VOC. It has been hypothesized that VOC and ACS represent different spectra of
the same disease process, as they are both associated with increased RBC sickling and localized vasoocclusion (1, 32). In
our patients, the only apparent factor favoring the formation of
isoprostanes was the presence of systemic hypoxemia. There
was no significant difference in the level of hemoglobin between these two groups, although in both it was lower, albeit
nonsignificantly, than in patients with SCD at baseline. It is
possible that the presence of reduced tissue oxygen delivery in
ACS favors the formation of oxygen-related radicals (8) that
can react with NO to form NO2, NO3, and ONOO (6). This
would result in enhanced lipid peroxidation and consequently
increased formation of isoprostanes. Once formed, the exact
mechanism of release of isoprostanes into the plasma is unclear, but may be due to the action of the phospholipases and/
or platelet activating factor (PAF)-acetyl hydrolases.
Another interesting finding in this patient group is the increase and individual variability in isoprostanes we observed
in patients with SCD at baseline compared with normal volunteers. This combined with the demonstration of an increase in
O2 and H2O2 in the RBCs of patients with SCD at baseline
(10, 11) suggests that there may be ongoing alterations in the
oxidative milieu in some of these patients even when they are
clinically asymptomatic (8, 9). Thus, subclinical episodes of
pulmonary vasoocclusion could occur in these patients and
play a role in the development of the chronic SC lung disease
characterized by pulmonary hypertension and cor pulmonale.
Several potential concerns are raised by this study. First is the possibility that the isoprostanes that are formed are not a result of lipid peroxidation, but are simply a marker of increased cyclooxygenase (COX) turnover, which has been demonstrated in patients with SCD (33). Although formation of isoprostanes via a COX-mediated mechanism can occur, it usually produces a trivial amount of these compounds (13). Thus, COX turnover is not likely to have produced the large increases in isoprostane levels we observed. Second, relatively few patients were studied and only three were sampled at more than one time-point. Future plans include a larger study evaluating patients with SCD over an extended time period to attempt to correlate levels of isoprostanes with clinical disease activity as well as measurement of isoprostane release from cultured endothelial cells exposed to sickle RBCs and/or plasma from patients with ACS.
In summary, there is a 9-fold increase in the plasma levels of F2 isoprostanes in patients with SCD during ACS. This suggests that there are alterations in the oxidant milieu in these patients and that the pathophysiology of ACS may, in part, relate to lipid peroxidation of the plasma membrane of the vascular endothelium leading to changes in endothelial cell metabolic function. Additionally, the isoprostanes that are formed may have a primary role in vasoconstriction. Further studies will be needed to determine if levels of isoprostanes in individual patients can be correlated with disease activity and reflect the response to administration of antioxidant medications.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Elizabeth S. Klings, M.D., The Pulmonary Center, R-304, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. E-mail: eklings{at}lung.bumc.bu.edu
(Received in original form January 5, 2001 and accepted in revised form July 9, 2001).
Deceased.
Dr. Klings is supported by a Research Training Fellowship from the American Lung Association RT-030-N. Dr. Christman is supported by NIH RO1-HL55198 and IP030 CA68485.
Acknowledgments:
The authors wish to thank Aileen Healy of the Pulmonary Center at Boston University for assistance with plasma preparation; Daniel Gottlieb and Suzette Levenson of the Boston University School of
Public Health for assistance with statistical analysis; and the nurses and staff
of the Sickle Cell Clinic and the Medical Intensive Care Unit at Boston Medical Center for assistance in care of the patients.
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METHODS
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DISCUSSION
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  C. R. Morris, J. H. Suh, W. Hagar, S. Larkin, D. A. Bland, M. H. Steinberg, E. P. Vichinsky, M. Shigenaga, B. Ames, F. A. Kuypers, et al. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease Blood, January 1, 2008; 111(1): 402 - 410. [Abstract] [Full Text] [PDF]
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M. L. Jison, P. J. Munson, J. J. Barb, A. F. Suffredini, S. Talwar, C. Logun, N. Raghavachari, J. H. Beigel, J. H. Shelhamer, R. L. Danner, et al. Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease Blood, July 1, 2004; 104(1): 270 - 280. [Abstract] [Full Text] [PDF]
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 C. R. Morris, S. M. Morris Jr., W. Hagar, J. van Warmerdam, S. Claster, D. Kepka-Lenhart, L. Machado, F. A. Kuypers, and E. P. Vichinsky Arginine Therapy: A New Treatment for Pulmonary Hypertension in Sickle Cell Disease? Am. J. Respir. Crit. Care Med., July 1, 2003; 168(1): 63 - 69. [Abstract] [Full Text] [PDF]
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 A K Siddiqui and S Ahmed Pulmonary manifestations of sickle cell disease Postgrad. Med. J., July 1, 2003; 79(933): 384 - 390. [Abstract] [Full Text] [PDF]
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 S. H. Salzman Does Splinting From Thoracic Bone Ischemia and Infarction Contribute to the Acute Chest Syndrome in Sickle Cell Disease? Chest, July 1, 2002; 122(1): 6 - 9. [Full Text] [PDF]
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M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
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