Open Journal of Respiratory Diseases, 2012, 2, 37-42
http://dx.doi.org/10.4236/ojrd.2012.22006 Published Online May 2012 (http://www.SciRP.org/journal/ojrd)
Influence of MnTE-2-PyP on Inflammation and Lipid
Peroxidation in Mouse Asthma Model
Lyudmil Terziev1, Veneta Shopova2, Violeta Dancheva2, Galya Stavreva3, Milena Atanasova4,
Angelina Stoyanova5, Tzvetan Lukanov1, Anelia Dimitrova6
1Sector of Clinical Immunology and Allergology, Medical University, Pleven, Bulgaria
2Sector of Disaster Medicine, Medical University, Pleven, Bulgaria
3Sector of Experimental and Clinical Pharmacology, Medical University, Pleven, Bulgaria
4Sector of Biology, Medical University, Pleven, Bulgaria
5Sector of Chemistry, Medical University, Pleven, Bulgaria
6Sector of Pathophysiology, Medical University, Pleven, Bulgaria
Received January 13, 2012; revised March 6, 2012; accepted March 15, 2012
Our aim was to investigate the effects of MnTE-2-PyP on some markers of inflammation and lipid peroxidation in
mouse asthma model. 24 female mice were divided into four groups: group 1, controls; group 2, injected with ovalbu-
min (OVA); group 3, treated with MnTE-2-PyP; and group 4, treated with ovalbumin and MnTE-2-PyP. The mice from
groups 2 and 4 were injected with 10 μg OVA and 1 mg Imject Alum® in 100 μL phosphate buffered saline (PBS) on
days 0 and 14. The animals from groups 1 and 3 were injected with 100 μL PBS + Imject Alum® (1:1). The animals
from groups 2 and 4 were subjected to a 30 min aerosol challenge of 1% ovalbumin on days 24, 25 and 26 and those
from groups 1 and 3 were subjected to aerosol challenge of PBS at the same time and duration. One hour before inhala-
tion, and 12 hours later the animals from groups 3 and 4 were injected with 100 μL MnTE-2-PyP solution in PBS con-
taining 5 mg/kg. The total cell number, total protein content and 8-isoprostane, IL-4 and IL-5 levels in the bronchial-
veolar lavage fluid increased in group 2 as compared to the control group. Malone dialdehyde content in the lung ho-
mogenate and IgE levels in the serum also increased in this group. The total cell number, total protein content, and lev-
els of 8-isoprostane, IL-4, IL-5 and IgE decreased significantly in group 4 as compared to the OVA group. The parame-
ters set out above in group 3 did not differ significantly from those of the control group. MnTE-2-PyP administered
intraperitoneally, 48 hours after the last nebulization, reduced the inflammation and lipid peroxidation in mouse asthma
Keywords: Asthma; Inflammation; Interleukins; 8-Isoprostane; Lipid Peroxidation; MnTE-2-PyP
Asthma is a lung disease characterized by airspace in-
flammation and oxidative stress [1-4]. Elevated levels of
reactive oxygen species (ROS), released by inflammatory
cells, either directly or through the formation of products
of lipid peroxidation, play a role in enhancing the in-
flammatory response in these diseases. The presence of
oxidative stress is important in the pathogenesis, severity
and treatment of asthma . Increasing evidence sug-
gests that abnormalities in mitochondria are involved in
several mitochondrial diseases, but also in the develop-
ment of asthma [6,7]. Recently, antioxidants to prevent
and to treat mitochondria in patients with mitochondrial
diseases, including asthma, has received much attention,
especially because antioxidant approaches seem to have
few or no adverse effects . Different classes of anti-
oxidants are known. Among them, the group of catalytic
manganese metalloporphyrins takes center stage with
their accumulation into mitochondria. They have at least
four antioxidant properties, such as removal of superox-
ide (), hydrogen peroxide (H2O2), peroxynitrite
(ONOO–), and lipoperoxides [9,10]. Based on this in-
formation, we set the goal to investigate the effects of
MnTE-2-PyP (Manganese(III) 5, 10, 15, 20-tetrakis (N-
ethylpyridinium-2-yl)porphyrin), a manganese-mesopor-
phyrin also known as AEOL-10113, on markers of in-
flammation and lipid peroxidation in a mouse ovalbumin
(OVA) sensitization model of asthma .
2. Materials and Methods
Ovalbumin, grade V, and phosphate buffered saline
(PBS), were purchased from Sigma-Aldrich Company,
Nitrocellulose filters with 5 μm pores were from Milli-
opyright © 2012 SciRes. OJRD
L. TERZIEV ET AL.
pore Corp, IL-4 and 5 ELISA Kits were from R&D Sys-
tems, 8-Isoprostane EIA Kit was from Cayman chemi-
cals, Mouse IgE ELISA Sets were purchased from BD
Biosciences, and the Imject Alum® was from the Pierce
Chemical Company (USA). MnTE-2-PyP was kindly
provided by Prof. Ines Batinić-Haberle from the Depart-
ment of Radiation Oncology, Duke University Medical
Center, Durham, North Carolina, USA.
2.2. Animals and Experimental Protocol
The experiment was performed in accordance with Ani-
mal Welfare Regulations and was approved by the Uni-
versity Ethics Committee.
The study was carried out on 24 female C57Bl/6 mice
(weight 20 ± 2 g, 8 - 10 week old). The animals were
raised at the University vivarium at a temperature of 22˚C
± 2˚C and humidity of 50% ± 10%, and were given a
normal pelleted diet and water ad libitum. The mice were
divided into four groups: group1, controls; group 2, in-
jected with ovalbumin; group 3, treated with MnTE-2-
PyP and group 4, treated with OVA and MnTE-2-PyP.
Airway inflammation was induced by OVA immuniza-
tion and challenge. The animals from groups 1 and 3 were
injected i.p. with a 100 μL phosphate-buffed saline (PBS)
+ Imject AlumR (1:1) on days 0 and 14. The animals from
groups 2 and 4 were injected with a 100 μL ovalbumin
solution, containing 20 μg OVA on the same days. On
days 24, 25 and 26, mice from groups 1 and 3 were given
inhalation with PBS for 30 min, and those from groups 2
and 4 were given inhalation with 1% ovalbumin solution
(OVA dissolved in PBS). For this purpose, a special
plexiglass chamber was used. One hour before inhalation,
and 12 hours later the animals from groups 1 and 2 were
injected i.p. with 100 μL PBS, and those from groups 3
and 4 received a 100 μL MnTE-2-Pyp dissolved in PBS,
containing 5 mg/kg, that is, the total daily dose was 10
The solution was sterilized by filtration through 0.2
2.3. Bronchoalveolar Lavage Fluid (BALF)
To obtain BALF, the animals were sacrificed on day 28
(48 hours after the last inhalation) under thiopental
anaesthesia (50 mg/kg). The chest was opened and the
lungs were perfused in situ via the right heart ventricle
with saline (10 mL). Triple lavage of the left lung through
the trachea was performed with a total volume of 2.5 mL
of saline. The right lung was ligated at the hilum, cut and
then removed from the chest and used to prepare the lung
Cytological, Biochemical and Immunological Assays
One aliquot of the BALF was used for the purpose of
total cell number × 105/mL. The cells were then removed
by centrifugation at 300 × g for 10 min. The supernatant
of BALF was used to measure interleukins and 8-iso-
prostane levels. The cell pellet was resuspended in 0.5
mL of saline, and differential cell count using Millipore
filters by the method of Danos and Keebler, modified by
Saltini  was performed. The total protein content in
ng/mL by the method of Lowry et al. , the levels of
IL-4 and IL-5 in pg/mL by the ELISA method, and the
level of 8-isoprostane in ng/mL by the ELISA method in
accordance with manufacturer’s instructions, were inves-
tigated in the supernatant of BALF.
2.4. Biochemical Assays of Lung Homogenate
Lung homogenate was obtained from the right lung. The
tissue was homogenized with potassium chloride (KCl)
in 1:10 ratio (lung mass by KCl solution volume). The
homogenate was centrifuged (9000 × g, 30 min), and the
supernatant was stored on ice. Malone dialdehyde (MDA)
content in nmol/g was measured by the method of Oh-
kawa et al. .
2.5. Immunological Assay of Serum
Blood was drown from the abdominal aorta by using
vacuum blood collection tubes. The blood was allowed to
clot for 30 minutes, and then centrifuged at 1000 × g for
10 min to achieve serum separation. The samples were
kept frozen at –20˚C until serum IgE analysis in ng/mL
was made by the ELISA method in accordance with
2.6. Statistical Analysis
Experimental data were analyzed using SPSS 14. When
we tested for normality, one variable-MDA showed non-
parametric distribution, and we used medians, interquar-
tile range and Mann-Whitney test for comparison. For
the rest of the variable we applied post-hoc ANOVA test
and data were presented as mean ± standart error of mean
(SEM). P < 0.05 was considered statistically significant.
The total cell number in group 2 (OVA-sensitized mice)
increased more than four fold in BALF (479% as com-
pared to the controls, P = 0.025). The increase of this
parameter in group 4 (OVA + MnTE-2-PyP) was sig-
nificantly lower (178%) than that in group 2. The eosi-
nophil percentage was 28% in group 2 and 18% in group
4, versus 0.5% in the control group (Table 1). The total
protein content in group 2 showed the same dynamics
(Table 1). The levels of IL-4 and IL-5 increased sharply
in group 2 (OVA) up to 1849% (P = 0.0006) and 350%
P = 0.016) respectively, in comparison with the control (
Copyright © 2012 SciRes. OJRD
L. TERZIEV ET AL.
Copyright © 2012 SciRes. OJRD
Table 1. Effect of MnTE-2-PyP on markers of inflammation in BALF and lipid peroxidation in lung homogenate in mouse
model of asthma.
28 day after treatment (48 hours after the last inhalation)
Parameters Control OVA MnTE-2-PyP OVA + MnTE-2-PyP
Total cell number in BALF (×105 mL) 2.26 ± 0.09 10.84 ± 2.34* 4.00 ± 0.40 4.04 ± 0.41†
AMas (%) 90.2 58.8 85.3 70.0
PMN (%) 4.6 8.2 5.5 5.8
Eo (%) 0.5 28.0 2.5 18.0
Total protein content (mg/mL) mean ± SEM 0.454 ± 0.025 0.563 ± 0.023* 0.419 ± 0.038 0.463 ± 0.050†
MDA content (n mol/g) Median 22.86 42.7* 22.68 20.86†
Min - max 21.56 - 26.88 39.2 - 46.20 15.12 - 32.48 19.04 - 22.68
Q3 - Q1 2.66 6.8 17.36 3.64
Abbreviations: OVA, ovalbumin; MnTE-2-PyP, Manganese(III) 5, 10, 15, 20-tetrakis(Nethylpyridinium-2-yl)porphyrin; AMas, alveolar macrophages; PMN,
polymorphonuclear leukocytes; Eo, eosinophils; IL-4 and IL-5, interleukins 4 and 5; IgE, immunoglobulin E; MDA, malone dialdehyde; SEM, standart error of
mean; Q3 - Q1, interquartile range. *: Different from control at P < 0.05; †: Different from group 2 (OVA) at P < 0.05.
group (Figures 1 and 2). OVA and antioxidant treatment
(group 4) decreased significantly these parameters as
compared to group 2 (OVA), up to 115% (P = 0.00003)
and 123% (P = 0.007) respectively. The IgE levels in the
group treated with OVA alone elevated up to 340% as
compared to the control animals (P = 0.00008). The in-
crease in group 4 (OVA + MnTE-2-PyP) was signifi-
cantly lower (264%, P = 0.049) as compared to group 2
(Figure 3). The changes in 8-isoprostane levels in BALF
and MDA content in lung homogenate, which are mark-
ers of lipid peroxidation, followed the same trend among
the four groups. The level of 8-isoprostane in group 2
was three times higher than that in the control group (P =
0.03), whereas in group 4 (treated with OVA and MnTE-
2-PyP) it was significantly lower than that in group 2,
and the values were approximate to those of the controls
(Figure 4). The MDA content increased up to 187% in
group 2 as compared to the control group. In group 4 this
content was approximate to that in the controls, and was
lower as compared to group 2 (P = 0.03), (Table 1). The
levels of interleukins and IgE as well as 8-isoprostane in
group 3 (MnTE-2-PyP alone) did not differ significantly
from those of control group.
The experimental data of our study showed that the
MnTE-2-PyP has a beneficial effect on the indicators of
inflammation and lipid peroxidation. Metaloporphyrins
are a new and potent class of lipid peroxidation inhibitors.
Their potency is connected not only to their redox poten-
tial, but also to other factors that can contribute to their
ability to act as electron acceptors. MnTE-2-PyP is very
effective in the elimination of reactive species, particu-
larly and ONOO−, with the highest rate constant
among the other synthetic antioxidants [15-18]. Manga-
nese(III) 5, 10, 15, 20-tetrakis(N-ethylpyridinium-2-yl)
porphyrin (MnTE-2-PyP) and Manganese(III) 5, 10, 15,
2-PyP) have an excellent SOD activity in vitro and in
vivo [19,20]. The biological role of MnTBAP and
MnTE-2-PyP is related to their peroxynitrite-binding
activity and reduction of the carbonate radical. Logcat
Figure 1. The level of IL-4 in BALF. Each point represents
the mean ± SEM for six mice.
Figure 2. The level of IL-5 in BALF. Each point represents
the mean ± SEM for six mice.
L. TERZIEV ET AL.
Figure 3. The level of IgE in serum. Each point represents
the mean ± SEM for six mice.
Figure 4. The level of 8-isoprostane in BALF. Each point
represents the mean ± SEM for six mice.
() of MnTBAP is about 3.16, which is about 5 - 6
times less-than the SOD activity of the powerful SOD
mimetic MnTE-2-PyP and CuZn SOD. Positively charged
MnTE-2-PyP and related analogues are very suitable for
SOD mimetics and ONOO–/ cleaners. MnTE-2-
PyP has a potent catalytic antioxidant-like effect of ex-
tracellular superoxide dismutase. The strong porphyrin-
based compounds are based on a “structure- activity” rela-
tionship, such as Mn(III) meso-tetreakis (N-ethylpyridi-
nium-2-yl)porphyrin (MnTE-2-PyP) and its hexyl ana-
logue (MnTnHex-2-PyP) .
We applied antioxidants in a dose of 10 mg/kg/daily,
divided into doses over 12 hours, starting with the asser-
tion that good tolerance in mice is observed at two doses
of 15 mg/kg/day and the plasma half-life varies consid-
erably. This is the most commonly used (as single or
multiple) therapeutic dose of this porphyrin . MnTE-
2-PyP administered i.p. or orally reaches maximum con-
centration in plasma in 0.33 hours [16,17]. It accumulates
at high levels in liver, kidney, and spleen, at moderate
levels in lungs and heart, and at low levels in brain. The
plasma half-life for a single i.p. dose of 10 mg/kg in mice
is about 1 hour and the half-life in the body is signifi-
cantly longer ranging from 60 - 135 hours [22-24]. Stud-
ies reveal that MnTBAP and MnTM-4-PyP are effective
in animal models of oxidative stress by forming super-
oxide [25-27], hydrogen peroxide [28,29] and peroxini-
ganese porphyrins have a molecular weight above 800,
quickly pass through cell membranes and are distributed
in mitochondria . MnTE-2-PyP in the liver cells
showed slightly higher accumulation in the mitochondria,
as compared with the cytosol (Spasojevich I., unpub-
trite [30,31]. Many water-soluble meso substituted man-
und not only decreases the primary insult
the financial support of
 P. Kirkham ane Stress in Asthma
reactive species to biological molecules, but also in-
hibits the activation of transcription factors which in turn
leads to suppression of expression of those cytokines and
enzymes that perpetuate secondary oxidative stress [20,32].
According to Gauter-Fleckenstein et al.  the inhabita-
tion of excessive cellular activity takes place through the
suppression of the transcriptional activity, particularly
suppressing HIF-1α (hypoxia inducible factor 1α) active-
tion in a long-lasting effect. Therefore reducing the total
number of cells, the amount of total protein observed
after treatment with mangan porphyrin can be explained
by the ability of the antioxidants to inhibit the expression
of VCAM-1 (vascular cell adhesion molecule-1) res-
ponsible for the accumulation of inflammatory cells, and
thus to decrease airway hyperreactivity . After intra-
tracheal introduction, the antioxidant dramatically re-
duces the severity of airway inflammation in the airways
in OVA-induced murine asthma. The reduction in the
number of eosinophils, neutrophils and lymphocytes in
BALF is more than 80% [34-36]. VCAM-1 and ICAM-1
(intra-cellular adhesion molecule) participate in the mi-
gration of eosinophils and neutrophils and contribute to
eosinophilic inflammation in animal models. MnTE-2-
PyP has been shown to alter cell signaling and reduce
inflammation by reducing NF-kB activity . Piganelli
et al. showed that MnTE-2-PyP inhibits T cell prolifera-
tion, while lipopolysaccha-ride-stimulated macrophages
treated with the compound, inhibit TNF-α (tumor necrosis
factor-α) and NADPH release of superoxide . The
beneficial effects of Mn alkylpyri-dylporphyrins have
been observed in various diseases, associated with oxida-
tive stress, such as radiation injury, Alzheimer’s disease,
cancer, diabetes, central nervous system injuries, ische-
mia/reperfusion conditions, pulmonary emphysema, and
other diseases [19,33,38-43].
This study was carried out with
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