Annals of Burns and Fire Disasters - vol. XXII - n.

1 - March 2009

BURNS, ENDOTHELIAL DYSFUNCTION, AND OXIDATIVE

STRESS: THE ROLE OF ANTIOXIDANTS

Sahib A.S.,1 Al-Jawad F.H.,2 Al-Kaisy A.A.3

1
Department of Pharmacology, Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq
2
Department of Pharmacology and Therapeutics, Al-Nahrain College of Medicine, Baghdad
3
Department of General Surgery, Baquba General Hospital, Diyala, Iraq

SUMMARY. Background. Burns cause a systemic inflammatory response, endothelial dysfunction, and increased microvascular
permeability which results in oedema being formed; these effects are probably the result of a complex interplay between the di-
rect effects of heat on the microcirculation and the action of chemical mediators, including reactive oxygen species. The use of an-
tioxidants can reduce these changes, which are considered a promised step in burns management. Patients and methods. Forty-eight
burn patients of either sex and with varying burns percentages were involved in the study. They were each allocated to one of four
groups: A, B, C, and D, each group composed of 12 patients. Groups B, C, and D were treated with antioxidants: allopurinol,
melatonin, and N-acetylcysteine respectively, while group A was treated according to normal hospital policy, without antioxidants;
12 healthy subjects (group E) served as a control group for comparison. In each group, serum malondialdehyde and serum glu-
tathione levels were measured and liver and kidney function tests were performed, as well as microalbuminuria tests, using stan-
dard methods. Results. The administration of antioxidants to burns patients produced significant improvements in the parameters
studied compared to group A parameters (no antioxidant given). Conclusion. This study clearly demonstrates the role of reactive
oxygen species in endothelial dysfunction occurring in burn patients and the beneficial effect of antioxidants in reducing it, as
shown by the reduced microalbuminuria and reduced resuscitation fluid in antioxidant-treated burn patients; the study also supports
newly emerging evidence regarding the use of microalbuminuria as an indicator for endothelial dysfunction in burn patients.

Introduction croalbuminuria in the very early post-burn period had po-

The pathophysiological mechanisms underlying the de-
velopment of oedema in burn patients are mainly due to
the inflammatory response which activates cytokines, with
subsequent stimulation of phagocytic cells. This results in
the formation of reactive oxygen species (ROS) leading to
lipid peroxidation; another source of ROS in burns is the
enzyme XO, produced from xanthine dehydrogenase un-
der ischaemic conditions producing ROS, which causes
lipid peroxidation.1 A close relationship has been demon-
strated between the intensity of lipid peroxidation and post-
burn complications, and it has been possible to document
the role of ROS leading to lipid peroxidation as a causative
agent in the mechanism of local and systemic complica-
tions in burns, including increased vascular permeability.2
The increase in vascular permeability leads to immediate
and continuous loss of substances ranging from water to
macromolecules.3 Generalized vascular permeability to
macromolecules has been described during surgery in an-
imal models, and microalbuminuria following acute in-
flammatory insults such as surgery has been demonstrat-
ed in human models, leading to the concept that microal-
buminuria is a reflection of systemic vascular endothelial
dysfunction.4 It was recently reported that monitoring mi-
tential as a sensitive and rapidly responding marker of sys-
temic endothelial dysfunction.5 It was also found that in-
creased microalbuminuria matched the severity of the in-
sult and correlated with the degree of organ failure - mi-
croalbuminuria reflects the evolution of systemic capillary
leakage and could be a useful parameter for assessing the
effectiveness of therapies for reducing endothelial dam-
age.6
Various antioxidants are used to antagonize ROS: al-
lopurinol, a well-known XO inhibitor;7 melatonin, a prod-
uct of the pineal gland that has powerful antioxidant ac-
tion through its direct scavenging effect and its stimula-
tion of antioxidant enzymes;8 and N-acetylcysteine, used
in the past as a mucolytic agent that rapidly metabolized
to cysteine, a direct precursor in the synthesis of intracel-
lular glutathione (GSH), the natural antioxidant.9 The in-
volvement of these antioxidants in burns treatment may
have improving effects on endothelial dysfunction and burn
outcome in general.
Patients and methods
The study was carried out on 48 burn patients of ei-
ther sex; the age range was 20-45 yr, and the burn per-

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 Annals of Burns and Fire Disasters - vol. XXII - n. 1 - March 2009

centage varied from 15 to 40% total body surface area

(TBSA), estimated according to the rule of nine.
The patients were allocated to four groups and treat-
ed as follows:
• Group A: 12 patients - this group was already present
in the burns unit and treated according to standard
hospital policy, by which antioxidants are not given
• Group B: 12 patients, treated with 100 mg/day al-
lopurinol tablet
• Group C: 12 patients, treated with 3 mg/day mela-
tonin capsule, taken at night
• Group D: 12 patients, treated with 500 mg/day N-
acetylcysteine capsule
A fifth group, Group E, consisting of 12 healthy sub-
jects in the same age range as the patients, served for con-
trol purposes.
All the treated groups received antioxidants in addi-
tion to other drugs prescribed according to the hospital
drug policy. Fig. 1 - Effects of antioxidants on serum malondialdehyde levels in
Blood samples were collected from all subjects by burn patients.
venipuncture: 10 ml were taken on admission to the burns A: No antioxidant. B: Allopurinol. C: Melatonin. D: N-acetylcyst-
eine. E: Healthy subjects.
unit within the first 24 h post-burn, before starting drug Discharge day in group A: after more than 3 weeks; other groups:
treatment (zero time), and then at days 3, 7, and discharge less than 2 weeks.
day in order to check any parameter changes. Urine sam-
ples were collected from all subjects at the same time pe-
riods, as also blood samples for microalbuminuria tests. With regard to serum GSH, Fig. 2 shows that serum
Serum malondialdehyde (MDA) levels were measured GSH levels were significantly reduced in burn patients at
according to the standard method of Stocks and Dor- zero time compared to healthy subjects; in group A, serum
mandy,10 as modified by Gilbert et al.11 Serum GSH levels GSH levels remained significantly lower than control un-
were measured using the method of Godin et al.;12 liver til discharge day, while in antioxidant-treated groups serum
enzyme activities (glutamate-pyruvate transaminase GSH levels were significantly increased at discharge day
(SGPT) and glutamate-oxaloacetate transaminase (SGOT) compared to zero time.
were calculated calorimetrically according to the method
of Reitman and Frankel;13 serum creatinine was determined
by the method of Henry;14 blood urea by that of Fawcett
and Scott;15 and microalbuminuria by that of McElderry et
al.,16 using for the purpose a ready-made kit. Statistical anal-
yses were performed using Student’s t-test and the
ANOVA test was used to examine the degree of signifi-
cance (p value less than 0.05 was considered significant).

Results

Results showed that serum MDA levels were signifi-

cantly increased (p < 0.05) at zero time in the burn pa-
tients compared to control; in group A (no antioxidant
used), serum MDA levels decreased nonsignificantly at day
3 and day 7 compared to zero time, but at discharge day
serum MDA levels decreased significantly by 62.2% com-
pared to zero time; this result was still significantly high- Fig. 2 - Effects of antioxidants on serum glutathione level in burn
patients.
er than in control group E (Fig. 1). Results in groups B, A: No antioxidant. B: Allopurinol. C: Melatonin. D: N-acetylcyst-
C, and D showed a significant reduction in serum MDA eine. E: Healthy subjects.
levels at day 7 and discharge day compared to zero time Discharge day in group A: after more than 3 weeks; other groups,
and group A (no antioxidant). less than 2 weeks.

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Annals of Burns and Fire Disasters - vol. XXII - n. 1 - March 2009

Figs. 3 and 4 show the changes in liver enzyme ac-

tivity, with significant increases in all the burn patients at
zero time; enzyme activity gradually returned to normal
levels at discharge day in group A; in the antioxidant-treat-
ed group, liver enzyme activity returned to normal levels
at day 3 post-burn - the same results profile as that ob-
tained for serum creatinine and blood urea (Fig. 5,6).
Fig. 7 shows a significant reduction (p < 0.05) in mi-
croalbuminuria levels in the antioxidant-treated groups (B,
C, and D) at day 3, compared to zero time - this reduc-
tion continued gradually down to the level of healthy con-
trol levels at discharge day, while in group A (no antiox-

Fig. 5 - Effects of antioxidants on blood urea in burn patients.

A: No antioxidant. B: Allopurinol. C: Melatonin. D: N-acetylcyst-
eine. E: Healthy subjects.
Discharge day in group A: after more than 3 weeks; other groups,
less than 2 weeks.

Fig. 3 - Effects of antioxidants on SGPT in burn patients.

A: No antioxidant. B: Allopurinol. C: Melatonin. D: N-acetylcyst-
eine. E: Healthy subjects.
Discharge day in group A: after more than 3 weeks; other groups,
less than 2 weeks.

Fig. 6 - Effects of antioxidants on serum creatinine in burn patients.

A: No antioxidant. B: Allopurinol. C: Melatonin. D: N-acetylcyst-
eine. E: Healthy subjects.
Discharge day in group A: after more than 3 weeks; other groups,
less than 2 weeks.

idant), the microalbuminuria level was still significantly

higher than control at zero time, day 3, and day 7 but on-
ly significantly reduced at discharge day, compared to ze-
ro time.

Discussion
Fig. 4 - Effects of antioxidants on SGOT in burn patients.
A: No antioxidant. B: Allopurinol. C: Melatonin. D: N-acetylcys- Thermal injury of the skin is an oxidation process, as-
teine. E: Healthy subjects.
Discharge day in group A: after more than 3 weeks; other groups, sociated with biological and metabolic alterations; it gen-
less than 2 weeks.

8

Fig. 7 - Effects of antioxidants on microalbuminuria in burn patients.
A: No antioxidant. B: Allopurinol. C: Melatonin. D: N-acetylcyst-
eine. E: Healthy subjects.
Discharge day in group A: after more than 3 weeks; other groups,
less than 2 weeks.
erates free radicals from various cellular populations by a
number of pathways; and the modulation of generated free
radical activity with antioxidants may improve outcome.17
In burn patients, alterations in antioxidant micronutri-
ent status and in endogenous antioxidant defences against
the deleterious effects of free radicals are crucial, as re-
cent studies have shown.18
It is known that circulating XO activity has been de-
tected during skin burns, and this is the greatest source of
free radicals in the serum of burn victims.19 Allopurinol,
and its principal metabolite, oxypurinol, inhibit the enzyme
XO, which catalyses the sequential oxidation of hypoxan-
thine to xanthine and of xanthine to uric acid,20 suggest-
ing that allopurinol may exert a beneficial action in is-
chaemia reperfusion injury, as is the case in burns.21
It has been reported that the pineal hormone melatonin
may function as a powerful antioxidant: it functions as a
scavenger of hydroxyl, peroxyl, and superoxide radicals,22
as also of hydrogen peroxide23 and peroxynitrite - the ug-
ly free radical.2 Melatonin is also able to stimulate the ac-
tivity of the antioxidant enzyme-like superoxyde dismu-
tase, catalase, GSH peroxidase, and GSH reductase;25 this
explains the strong indication of melatonin as a rational
antioxidant therapy in the treatment of burns - the rich free
radical environment.
With regard to N-acetylcysteine’s antioxidant, it has
been shown that N-acetylcysteine acts as a source of sul-
phydryl groups and facilitates GSH synthesis, in addition
to being a direct scavenger for ROS.26
The data obtained in the present study regarding re-
duction of the MDA serum level and elevation of the serum
Annals of Burns and Fire Disasters - vol. XXII - n. 1 - March 2009
GSH level - the natural antioxidant - in burn patients are
clearly compatible with the results obtained by other re-
searchers.
Increased liver enzyme activity reflects cellular dam-
age due to a burn - it is widely believed that enzyme ac-
tivity normalizes before patients are discharged.27 The same
observation was made in investigations of blood urea and
serum creatinine in burn patients.28 It has also been shown
that an increased concentration of the lipid peroxidation
product MDA in the early post-burn period can affect the
liver and kidney, resulting in the release of enzymes into
the blood stream, and that this damage can be remedied
with antioxidant, resulting in a return of enzymes to nor-
mal levels.29 This is exactly what happened in this study -
precisely the same thing occurred as regards blood urea
and serum creatinine.
The vascular endothelium, which regulates the passage
of macromolecules and circulating cells from blood to tis-
sues, is a major target of oxidant stress, playing a critical
role in the pathophysiology of several vascular diseases.
Oxidative stress increases vascular endothelial permeabil-
ity and promotes leukocyte adhesion - these are coupled
with alterations in endothelial signal transduction and the
redox-regulated transcription factor such as NF-kB.30 Re-
sults obtained by Giner et al.31 in hypertensive patients
showed that in microalbuminuric subjects the amount of
reduced GSH was significantly lower than in normoalbu-
minuric subjects, which is compatible with the results of
this study, as shown in Figs. 2 and 7. It has been sug-
gested that reactive oxygen intermediate and reactive ni-
trogen intermediate are the final common pathway leading
to endothelial cell dysfunction, premature endothelial cell
senescence, and apoptosis, and that antioxidants represent
an important therapeutic strategy for the prevention and
correction of endothelial dysfunction.32
It has been reported that oxidants produced endothe-
lial redox imbalance and loss of vascular integrity by dis-
organizing several junctional proteins that contribute to the
maintenance and regulation of the endothelial barrier; en-
dothelial cell permeability significantly increased as a re-
sponse to chemical redox imbalance; thiol depletion also
resulted in disruption of the endothelial barrier; and the
deleterious effects of intracellular redox imbalance were
blocked by treatment with exogenous GSH.33
In vascular endothelial cells, the cross-bridge move-
ment between actin and myosin occurs via myosin light
chain kinase (MLCK)-catalysed phosphorylation of the reg-
ulatory myosin light chain. This reaction results in cell
contraction and opening of the intercellular junctions, fa-
cilitating the paracellular flux of fluid and macromolecules
across the endothelium. Inflammatory agonists, including
histamine, cytokines, ROS, and neutrophils, are capable of
inducing MLCK activation concomitantly with endothelial
hyperpermeability. Typical hyperpermeability factors like
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Annals of Burns and Fire Disasters - vol. XXII - n. 1 - March 2009

ROS are potent activators of MLCK, and antioxidants may
act to block myosin light chain phosphorylation, which
may provide therapeutic intervention in burn patients with
a goal of alleviating systemic inflammation-induced en-
dothelial dysfunction.34
Data obtained in the present study show that treatment
with antioxidants (groups B, C, and D) results in a re-
duction of resuscitation fluid from 4 ml/kg/% burn to 1
ml/kg/% burn, compared to the non-antioxidant-treated
patients (group A), who received 4 ml/kg/% burn; this re-
sult may be supported by the data shown in Fig. 7 that in-
dicate that microalbuminuria decreased significantly at day
3 post-burn in all antioxidant-treated groups, but not in
group A where no antioxidant was used - this may explain
the role of antioxidants in preventing endothelial dysfunc-
tion, increased microvascular permeability, and fluid loss.
On the other hand, results obtained by Till et al.35
demonstrated that, after thermal injury, permeability
changes and oedema formation progressed over time, with
peak changes occurring 60 min after thermal trauma; the
plasma of thermally injured rats showed dramatic increas-
es in the levels of XO activity, with peak values appear-
ing as early as 15 min after thermal trauma - it has been
suggested that vascular injury defined by increased vas-
cular permeability is related to the activation of XO and
to the generation of toxic metabolites that damage mi-
crovascular endothelial cells. Also, Berry and Hare36
showed that in ischaemia-reperfusion injury XO partici-
pated in endothelial dysfunction and that, in these condi-
tions, XO inhibitors like allopurinol and oxypurinol atten-
uated the dysfunction.
Conclusion
In conclusion, the results of this study strongly sug-
gest the role of reactive oxygen species in the endothelial
dysfunction that occurs in burn patients and the beneficial
role of antioxidants in the reduction of this endothelial dys-
function, as represented by a reduction in microalbumin-
uria and a reduction of resuscitation fluid in antioxidant-
treated burn patients. The results of the study also support
the newly emerging evidence regarding the use of mi-
croalbuminuria as an indicator for endothelial dysfunction
occurring in burn patients.

RÉSUMÉ. Eléments de base. Les brûlures provoquent une réaction inflammatoire systémique, un dysfonctionnement endothélial
et un incrément de la perméabilité microvasculaire qui porte à la formation d’oedèmes; ces effets sont probablement le résultat
d’une interaction complexe entre les effets directs de la chaleur sur la microcirculation et l’action de médiateurs chimiques, y com-
pris les espèces réactives oxygénées. L’utilisation des antioxydants peut réduire ces modifications, qui sont considérées le déve-
loppement futur de la gestion des brûlures. Patients et méthodes. Quarante-huit patients brûlés de l’un et l’autre sexe atteints de
brûlure d’extension variable ont été inclus dans l’étude. Les patients ont été assignés à un de quatre groupes: A, B, C et D (chaque
groupe était composé de 12 malades). Les patients des groupes B, C et D ont été traités avec des antioxydants: allopurinol, méla-
tonine et N-acétylcystéine respectivement, tandis que le groupe A a été traité selon la normale politique de l’hôpital, c’est-à-dire
sans antioxydant; en outre, 12 sujets sains (groupe E) ont été utilisés comme groupe témoin pour comparaison. Dans chaque grou-
pe, les niveaux de malondialdéhyde du sérum et de glutathione du sérum ont été évalués et la fonction hépatique et rénale a été
évaluée moyennant les méthodes standard; aussi la microalbuminurie a été évaluée. Résultats. L’administration d’antioxydants aux
patients brûlés a produit une amélioration considérable dans les paramètres étudiés par rapport aux paramètres du groupe A (au-
cun antioxydant administré). Conclusion. Cette étude démontre clairement le rôle des espèces réactives oxygénées dans le dys-
fonctionnement endothélial qui se produit dans les patients brûlés et l’effet salutaire des antioxydants dans la réduction de ce type
de dysfonctionnement endothélial, un résultat démontré par la réduction de la microalbuminurie et de la fluidothérapie pour les pa-
tients brûlés traités avec les antioxydants; cette étude en outre confirme des résultats récents qui concernent l’emploi de la micro-
albuminurie comme indicateur du dysfonctionnement endothélial des patients brûlés.

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This paper was received on 29 January 2009.
Address correspondence to: Dr Ahmed Salih Sahib,
Department of Pharmacology, Al-Kindy College of
Medicine, Baghdad, Iraq.
E-mail: ahmedsalih73@yahoo.com
11