Comparison of Glutathione Peroxidase Activity and Free Radicals Production in the Lungs and the Brain of Rats During Graded Hyperoxia
The purpose of this study was to examine the behavior of glutathione
peroxidase (GPx) activities and Free Radicals (FR) production in the brain
and the lung during graded hyperoxia exposure. Twenty-four adult male
rats, matched with age and body weigh, were randomly assigned to four
groups. The first group served as control and the second, third and fourth
were exposed to hyperoxia for 24, 48 and 72 h, respectively. Following
the exposure period for each group animals were sacrificed and both lungs
and brain tissues were homogenized for GPx and FR determinations. GPx
activity was determined by Randox protocol (Randox, UK) and FR was determined
using dROM method (H and D, Italy). Results showed that mean ( ±
SD) GPx activity in the lungs increased from the baseline control of 12898.33
± 6034.77 to 20083.62 ± 2734 (U L-1) during hyperoxia
exposure for 24; then dropped to 5467.77 ± 1159.53 and 8271.80
± 1347.67 (U L-1) during hyperoxia exposure for 48 and
72 h, respectively. Whereas mean ( ± SD) GPx activity in the brain
increased from the baseline control of 5467.80 ± 2852.65 to 13841.72
± 1245.67 and 14594.82 ± 6711.44 (U L-1), during
hyperoxia exposure for 24 and 48 h, respectively; then dropped to 4346.17
± 343.34 (U L-1), during 72 h exposure. The sustained
increased in GPx up-to 48 hr in the brain provided evidence of delayed
protection against ROS. The average ( ± SD) FR production in the
lung increased from the baseline control of 176.67 ± 33.79 to 274.33
± 33.37, 260.00 ± 62.54 and 320.00 ± 114.91 (U L-1)
during hyperoxia exposure for 24, 48 and 72 h, respectively. The average
( ± SD) FR production in the brain increased from the baseline
control of 73.33 ± 20.18 to 132.17 ± 21.77 during hyperoxia
exposure for 24 h and then dropped to 94.33 ± 14.56 and 65.33 ±
21.12, during 48 and 72 h, respectively. Tukey-Kramer multiple comparisons
between the lung and the brain showed that the lungs had higher rate of
FR formation at all levels of hyperoxia exposures, which suggest more
mechanisms that had contributed to FR formation in pnueumocyte, as compared
with neurocyte. Based on the results of the present study antioxidant
supplements are recommended for traumatic brain injury and hypoxemia lung
injury patients subjected to oxygen therapy.
Oxygen toxicity had attracted the attention in physiology since the early
work by Bean (1945) and Comroe et al. (1945). Hyperoxia inducts
reactive oxygen species (Heberlein et al., 2000; Hitka et al.,
2003; Haffor and Al-Johany, 2005) which alter cellular components and
thus impair various ionic conductance`s that regulate cell excitability
and exchangeability (Colton and Colton, 1986; Upham et al., 1997;
Bickford et al., 1999). Studies of hyperoxia confirmed that ROS
are reported to target certain neurotransmitter and neuromodulator systems
and thus to alter chemical synaptic function (Zhang et al., 1995;
Bitterman and Bitterman, 1998; Dean and Mulkey, 2000; Mulkey et al.,
2003). Following exposure to hyperoxia, the lungs show morphologic changes
that are similar to pulmonary inflammation, atelectasis and oedema formation,
leading to irreversible loss of respiratory function. Furthermore, lung
inflammation is associated with infiltration of circulating neutrophils
(Crapo, 1986; Jankov et al., 2003; Jafari et al., 2004)
with potential source for ROS formation.
Glutathione Peroxidase (GPx), is a free radical scavenger, initially
reported that neutralized the highly toxic hydroxyl radical (Paglia and
Valentine, 1967), an observation which has been confirmed by several authors
(Allen and Balin, 2003; Pollack et al., 2005; Al-Johany and Haffor,
2007). Previous studies demonstrated that GPx is critical antioxidant
in the peroxidase system of cytochrome-C, quinones and ascrobate that
prevented mitochondrial swelling which are accompanied by the production
of hydrogen peroxide and malonaldhyde and intermediate of free radicals
initiated lipid peroxidation (Hunter et al., 1964; Lesnefsky et
al., 2001; Haffor et al., 2002; Haffor, 2004; Haffor and Al-Johang,
2005; Haffor and Alhazza, 2007).
The question that arises is how fast it takes for ROS intermediates to
react with membrane lipids and start a series of pathologic antioxidants
response in the brain, as compared with the lung tissues. The clinical
relevance of this issue relates to the controversial question of whether
hyperoxic exposure intervals contribute to irreversible deleterious in
the CNS control of pulmonary vascular effects or an earlier direct pneumocyte
phagocyte infiltration mechanism. The purpose of this study was to examine
the changes in glutathione peroxidase activity (GPx) and free radicals
(FR) production in the brain and the lung tissues during graded hyperoxia
exposure for 24, 48 and 72 h. In particular, we emphasize the use of hyperoxia
under normal baric O2 as in intensive care model for studying
the impact on the cellular mechanisms by which acute oxidative stress
(ROS) can potentially alters neuronal and pneumocyte physiological activities.
Some of this work has been published previously in abstract form (Bin-Jaliah,
MATERIALS AND METHODS
Experimental design and hyperoxia exposure: The experiments were
conducted during the spring of 2007 in the College of Science, King Saud
University, as part of collaborative initiative with the aim to establish
a High Altitude and Stress Physiology Laboratory (HASPL). Twenty-four
adult wister albino male rats, Rattus norvigicus, matched with
age and body weigh were randomly assigned to four groups, six animals
each. The first group served as control and the second, third and fourth
were exposed to hyperoxia for 24, 48 and 72 h, respectively. Animals of
the experimental groups were placed in a closed box that has an inlet
flow which was connected to 100% O2 tank, medical grade, on
which a regulator was connected to maintain flow at 5 L min-1
(LPM). The out flow of the regulator passed through a humidifier in order
to saturate the inspired air with H2O. The outlet ventilation
rate of the box was adjusted at 5 LPM to ensure that the concentration
of oxygen in the box remains equal to 100% O2 and maintain
normal flow and normal barometric pressure at 767 mmHg. The temperature
inside the box was adjusted at room temperature (22-24° C). Animals
of the control and experimental groups were sacrificed and the lungs and
brain were isolated and homogenized immediately in 0.9 saline solutions
Glutathione peroxidase: Samples from all groups were used for
the determination of GPx activities using Randox protocol (Randox, England).
This method is based on the detoxification of hydrogen peroxide by the
oxidation of reduced glutathione according to the following reaction:
Free radical determination: Free radicals production was measured,
using the d-ROMs-2 test kits (Health and Diagnostic, Italy) according
to the manufacturer`s instructions. The test measures the levels of hydroperoxides
(R-OOH) which are generated by peroxidation of biological compounds; lipid,
amino acids, nucleic acids. This test is based on the principle of the
ability of hydrogen peroxides to generate free radicals after reacting
with some transitional metals (Fe2+/Fe3+),
according to Fenton`s Reaction as follows:
H2O2 + Fe++
= *OH + OH– + Fe++
Thus, the hydrogen peroxides of biological sample (whole blood) generate
free radicals (alcoxy and peroxyl radicals) after exposure to a transitional
metal (Fe++/Fe+++). When a correctly buffered chromogen
substance (N, N-diethyl-phenylenediamine) lead to the reduction of hydrogen
peroxides which in turns colored as radical cation. Color intensity was
read using spectrophotometer with peak absorbance of 505 nm. In the d-ROMs
test, results were expressed in CARR units (CARR U). One CARR U relates
to 0.08 mg H2O2/100 mL.
Statistical analysis: Mean group differences for the dependent
variables; glutathione peroxidase (GPx) and free radicals (FR) were evaluated
using one-way analysis of variance (ANOVA) to reveal the main effect of
each group on the dependent variables. Tukey-Kramer multiple comparisons
were used to compare differences between each means pairs.
The mean final body weights ( ± SD) of the four groups; control,
hyperoxia-24 h, hyperoxia-48 h and hyperoxia-72 h; at the end of the experiment
were 185.67 ± 6.41, 188.66 ± 11.39, 192.33 ± 10.09
and 186.83 ± 12.35 g, respectively. Results of paired t-test indicated
that values were not significantly (p>0.05) different from body weights
prior to the experiment.
Exposure to hyperoxia resulted in increasing mean ( ± SD) GPx
activity from the baseline control of 12898.33 ± 6034.77 to 20083.62
± 2734 (U L-1), during hyperoxia exposure for 24; then
dropped to 5467.77 ± 1159.53 and 8271.80 ± 1347.67 (U L-1),
during hyperoxia exposure for 48 and 72 h, respectively. The average (
± SD) FR production in the lung increased from the baseline control
of 176.67 ± 33.79 to 274.33 ± 33.37, 260.00 ± 62.54
and 320.00 ± 114.91 (CARR) during hyperoxia exposure for 24, 48
and 72 h, respectively (Table 1).
GPx activity in the brain increased, from the mean baseline control of
5467.80 ± 2852.65 to 13841.72 ± 1245.67 and 14594.82 ±
6711.44 (U L-1), during hyperoxia exposure for 24 and 48 h,
respectively; then dropped to 4346.17+343.34 (U L-1), during
72 h exposure. The mean ( ± SD) FR production in the brain increased
from the baseline control of 73.33 ± 20.18 to 132.17 ± 21.77
during hyperoxia exposure for 24 h and then dropped to 94.33 ±
14.56 and 65.33 ± 21.12, during 48 and 72 h, respectively (Table
Results of one-way (ANOVA) analysis of variances (Table
3) showed significant (p<0.05) differences among groups` means
in both lungs and brain for glutathione peroxidase (GPx) activities and
free radicals (FR) productions. Post-hoc Tukey-Kramer multiple comparisons
procedures (Table 4) were conducted to simultaneously
examine comparisons between all possible pairs of group means. When hyperoxia
exposure administered for 24 h, it elevated GPx activity significantly
(p<0.05), then dropped significantly (p<0.05) at 48 h in the lungs
and remained lower following 72 h exposure but the difference was not
statistically significantly (p>0.05) lower than control group. In the
brain, when hyperoxia was administered for 24 h, it elevated GPx significantly
(p<0.05) and remained higher significantly (p<0.05) following hyperoxia
exposure for 48 h, then dropped to control value following 72 h of hyperoxia
exposure. Despite the observed progressive rise in FR production in the
lungs, with increasing hyperoxia exposure but the difference was significantly
(p<0.05) higher following hyperoxia exposure for 72 h only. In the
brain, when hyperoxia administered for 24 h FR production increased significantly
(p<0.05), then dropped following exposure for 48 and 72 h, but the
difference was not statistically significant (p>0.05), as compared
with control group. Figure 1a and b displays and summarizes
the behavioral mean changes for GPX activity and FR production in the
lungs and the brain during control and hyperoxia exposure for 24, 48 and
|| Glutathione peroxidase activity (U L-1)
and free radicals production (Carr) in the lungs
|| Glutathione peroxidase activity (U L-1)
and free radicals production (Carr) in the brain
|| One way analysis of variance (ANOVA) results
|| Tukey-Kramer Multiple comparisons for GPx and FR in
the lungs and brain
|*Group 1 = Control, Group 2 = Hyperoxia exposure for
24 h, Group 3 = Hyperoxia exposure for 48 h and Group 4 = hyperoxia
exposure for 72 h
||The Behavior of mean GPx in the lungs and brain (a)
and FR production in the lungs and brain (b) during hyperoxia exposure
Hyperoxia is believed to generate Reactive Oxygen Species (ROS) and inhibit
antioxidants defense. O2 toxicity is believed to occur when
the body`s antioxidant defenses are overwhelmed by increased production
of ROS. Included in ROS list are superoxide, hydrogen peroxide, hydroxyl
radicals and peroxynitrite at high levels of PtiO2 (Demchenko
et al., 2001, 2003; Elayan et al., 2000; Torbati et
al., 1992). Herein, the present study showed that glutathione peroxidase
(GPx) in the lungs was overwhelmed following 24 h of hyperoxia exposure.
In the brain, GPx was overwhelmed after 48 h of hyperoxia exposure.
It is clear that dysfunctional mitochondria result in releasing its contents
such as oxidative enzymes and hydrogen peroxides to the cytoplasm, in
attempt to prevent swelling. When the rate of release of mitochondrial
contents exceeds elimination rate of antioxidants defense system, ROS
accumulate and FR productions rise. GPx catalyzes specifically detoxification
of hydrogen peroxide (Paglia and Valentine, 1967). The severity of hyperoxic-induced
cellular injury is time and dose dependent (Hayatdavoudi et al.,
1981; Barry and Crapo, 1985; Crapo et al., 1994).
The effects of hyperoxia on the central nervous system (CNS) and risk
of bronchopulmonary dysplasia in infants or adult respiratory distress
syndrome in adults begins with exposure period over 8 hours (Arieli, 1998;
Chavko et al., 1998; Demchenko et al., 2001). In healthy
adult risk begins after 48 h (Comroe et al., 1945). Acute exposure
to hyperoxia causes tissue and cellular damages in the brain (Huang et
al., 2000; Gerstner et al., 2006). In addition, ethanol intake
is associated with adaptive changes in the antioxidant defense enzymes
such as increased levels of neural superoxide dismutase and catalase (Montoliu
et al., 1994). Furthermore, chronic ethanol intake decreases the
levels of the GSH (Guerri and Grisolia, 1980; Montoliu et al.,
1994) and tocopherol content of the cerebellum (Rouach et al.,
1991). Many clinicians have successfully reduced oxygen toxicity by the
antioxidant redoxiredoxin administration (Kim et al., 2003) and
selenium supplementation (Ebert et al., 2006). Others used nitro
oxide to prevent cell apoptosis in the lungs (Iben et al., 2000;
Howlett et al., 1999). In the present study, GPx sustained its
rise in attempt to defend the integrity of the pneumocyte till 24 h of
hyperoxia exposure and up-to 48 h in the brain.
Although increased generation of ROS is evident in lung epithelia cells
in vitro within 30-60 min of hyperoxia (Manautou and Carlson, 1991;
Sanders et al., 1993; Parinandi et al., 2003), clinical
use of normobaric hyperoxia for several hours is frequently considered
harmless or even recommended to reduce the risk of post-surgical wound
infections (Neubauer et al., 1994; Greif et al., 2000; Belda
et al., 2005) and head injury (Brown et al., 1988). In humans,
the first respiratory symptoms have been reported after 6 h of oxygen
exposure (Comroe et al., 1945) and ultrastructural alterations
such as epithelial cell swelling are evident within 14 h but with hyperoxia
of 70% O2 (Kapanci et al., 1972). In rats, animals die
within 60-72 h of exposure to 100% O2, whereas an FIO2
of 0.85 is sublethal but may cause platelet accumulation within
3 days and increase lung weight within 5 days of exposure (Crapo et
al., 1980; Barry and Crapo, 1985; Tibbles and Edelsberg, 1996). Herein,
results of the present study clearly showed reduction in GPx and higher
rate of FR generation beyond 24 h of hyperoxia exposure (100% O2,
medical grade) but did not result in animals` death up-to 72 h.
The severity of hyperoxic lung injury is time- and dose dependent (Crapo
et al., 1980; Barry and Crapo, 1985). As compared with 95% O2
, an FIO2 of 0.7 results in less ROS formation but does
not protect from lung injury when applied over longer periods because
rats exposed to 60% O2 for 7 days showed reduced lung compliance
and perivascular oedema formation (Cragg et al., 1986; Caldwell
et al., 1966; Nishio et al., 1998) and 14 day exposure to
60% O2 causes low-grade epithelial injury and interstitial
fibrosis in baboons (Crapo et al., 1994). Besides lung epithelial
ROS generation, capillary endothelial cells were identified as the source
of hyperoxia-induced ROS production (Kuebler et al., 2000). Herein,
results of the present study showed a steady rise in ROS generation, along
with increasing exposure period, yet beyond the onset of lung tissue injury
at 24 h, which reflected additional phagocytes defense mechanism of the
alveolar macrophages which in turn contributed additively to ROS generation.
The results of the present study along with the data showing that GPx
and FR levels increased in the lungs and the brain tissues but these changes
were delayed and reversed in the brain. Steady elevated of ROS formation,
with increasing exposure period, in the lungs reflected added pulmonary
vascular effects directly related to pneumocyte phagocyte infiltration
mechanism, perhaps ROS-related chemotaxic mechanism.
The author thanks Dr. Al-Said Haffor from the College of Science, King
Saud University for his sincere help in data management, analysis and
review of this manuscript.
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