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Cumulative effect of systemic inflammation and oxidative stress in 40 known cases of active rheumatoid arthritis

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Abstract

p class="abstract"> Background: Oxidative stress has been implicated in the pathophysiology of a number of diseases such as cancer, hypertension and inflammatory diseases. Although previous evidences provided extensive literature about the biological role of antioxidant enzymes in rheumatoid arthritis (RA), there is a paucity of satisfactory explanation regarding the alteration in the level of antioxidant enzymes along with marker of systemic inflammation in RA. The objective of present study was to estimate the level of C-reactive protein (CRP), Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GSHPx) and Ceruloplasmin in active RA patients. Methods: 40 patients of either sex (30-50 years age group) suffering from active RA and 40 normal healthy individuals served as control; were included in the study. Above mentioned parameters were estimated using standard methods and data from patients and controls were compared by using Student’s t-test. Results: Erythrocyte SOD, CAT and GSHPx activity were significantly low in RA subjects (P<0.001) whereas plasma Ceruloplasmin level was found to be significantly high (P<0.001) as compared to healthy controls. Conclusions: These findings suggest that combined effect of inflammation and free radical generation is involved in the pathogenesis of active RA, characterized by imbalance in antioxidant enzyme status and enhanced CRP levels, which served as an excellent marker of oxidative stress and systemic inflammation in active RA.</p
International Journal of Research in Orthopaedics | October-December 2015 | Vol 1 | Issue 1 Page 7
International Journal of Research in Orthopaedics
Saxena R et al. Int J Res Orthop. 2015 Dec;1(1):7-10
http://www.ijoro.org
Research Article
Cumulative effect of systemic inflammation and oxidative stress in 40
known cases of active rheumatoid arthritis
Rahul Saxena1*, Shilpa Suneja2, Raj Saxena3, Dilutpal Sharma4, Alok Milton Lal5
INTRODUCTION
Contrary to common belief rheumatoid arthritis is not a
trivial illness but a major medical condition that affects
the quality of human life of developed and developing
countries as well.1 Previous evidences suggest that
reactive oxygen species derived from molecular oxygen
(Superoxide anion, hydrogen peroxide and hydroxyl
radical) contribute to the tissue injury, which
accompanies inflammatory disorders including
rheumatoid arthritis and osteoarthritis.2,3 A number of
sources of free radical generation have been identified in
biological tissues, which may be mutually interactive and
once triggered, they may lead to loss of antioxidant
defense system. The defense system to combat the
potentially damaging effects of free radical species
includes antioxidant enzymes and antioxidants.
Superoxide dismutase (SOD, EC: 1.15.1.1), Catalase
(CAT, EC: 1.11.1.6), Glutathione peroxidase (GSHPx,
EC: 1.11.19) and Ceruloplasmin (EC: 1.16.3.1). SOD
catalyses the conversion of superoxide radicals to
hydrogen peroxide and molecular oxygen. Hydrogen
peroxide is further detoxified by either heme containing
enzyme CAT or selenium containing enzyme GSHPx.
ABSTRACT
Background: Oxidative stress has been implicated in the pathophysiology of a number of diseases such as cancer,
hypertension and inflammatory diseases. Although previous evidences provided extensive literature about the
biological role of antioxidant enzymes in rheumatoid arthritis (RA), there is a paucity of satisfactory explanation
regarding the alteration in the level of antioxidant enzymes along with marker of systemic inflammation in RA. The
objective of present study was to estimate the level of C-reactive protein (CRP), Superoxide dismutase (SOD),
Catalase (CAT), Glutathione peroxidase (GSHPx) and Ceruloplasmin in active RA patients.
Methods: 40 patients of either sex (30-50 years age group) suffering from active RA and 40 normal healthy
individuals served as control; were included in the study. Above mentioned parameters were estimated using standard
methods and data from patients and controls were compared by using Student’s t-test.
Results: Erythrocyte SOD, CAT and GSHPx activity were significantly low in RA subjects (P<0.001) whereas
plasma Ceruloplasmin level was found to be significantly high (P<0.001) as compared to healthy controls.
Conclusions: These findings suggest that combined effect of inflammation and free radical generation is involved in
the pathogenesis of active RA, characterized by imbalance in antioxidant enzyme status and enhanced CRP levels,
which served as an excellent marker of oxidative stress and systemic inflammation in active RA.
Keywords: Superoxide dismutase, Catalase, Ceruloplasmin, C-reactive protein, Free radical
1Department of Biochemistry, SAHS, Sharda University, Greater Noida, UP, India
2Department of Biochemistry, VMMC & Safdarjung Hospital, New Delhi, India
3Department of Clinical Research, Sikkim Manipal University, Manipal, India
4Department of Biochemistry, Kings George Medical College, Lucknow, UP, India
5Department of Biochemistry & Biochemical Engineering, JSB & B, SHIATS, Allahabad, UP, India
Received: 15 October 2015
Accepted: 21 November 2015
*Correspondence:
Dr. Rahul Saxena,
E-mail: rahulapril@gmail.com
Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: http://dx.doi.org/10.18203/issn.2455-4510.IntJResOrthop20160341
Saxena R et al. Int J Res Orthop. 2015 Dec;1(1):7-10
International Journal of Research in Orthopaedics | October-December 2015 | Vol 1 | Issue 1 Page 8
Ceruloplasmin, is a blue colored copper binding protein,
function as antioxidant enzyme by virtue of its
ferroxidase activity and scavenges superoxide anion
radical.4,5
Alterations in the levels of these antioxidant enzymes
with subsequent biomolecular deterioration via increased
ROS production can cause cartilage collagen degradation,
loss of homeostasis in chondrocytes leading to impaired
chondrocyte function, destructive changes in extracellular
matrix, synovitis and cartilage ageing, and thereby
perpetuate arthritis development. Moreover, free radicals
mediated oxidative stress has been described as an
important mechanism underlying destructive proliferative
synovitis in arthritic patients.6 C-reactive protein (CRP), a
marker of systemic inflammation and synthesized in
liver, has been received considering attention in
inflammatory disorders such as rheumatoid arthritis. In
addition, previous studies have demonstrated an
association between arthritis progression and
inflammation as measured by plasma C-reactive protein.7
Although several evidences provided extensive literature
about the role of antioxidant enzymes and inflammation
in arthritis, there is a paucity of satisfactory explanation
regarding, alteration in the level of these antioxidant
enzymes and systemic inflammation in active RA. In
addition, as best of our knowledge, previous studies on
active RA patients have not included systemic
inflammation and oxidative stress in a single setting
Therefore, the objective of present study was to estimate
the level of these antioxidant enzymes and systemic
inflammation in active RA patients and statistically
determine the variation in their level by comparing it with
that of healthy subjects served as control.
METHODS
In the present study 40 patients of either sex with active
rheumatoid arthritis belonged to age group 30-50 years
and 40 age matched healthy individuals, served as
control, were taken. A general information or pre-
experimental questionnaire regarding demographic
information, family history and limited physical
examination including blood pressure measurement was
completed from all the subjects after taking their
informed consent and approval of protocol by ethics
committee of college. All patients had active RA, defined
as the presence of at least three of the following criteria:
six or more tender joints; three or more swollen joints;
30 min of morning stiffness; an erythrocyte
sedimentation rate of 28 mm/h.
Inclusion criteria
Subjects, who gave informed consent for study, having
no history of any type of arthritis, don’t under any
medical treatment (anti-inflammatory drug) or taking
antioxidant supplement for at least 1 month prior to blood
collection were included.
Exclusion criteria
Patients with diabetes mellitus, hepatic disease,
hypertension, those taking antioxidant vitamin
supplements or non-steroidal antiinflammatory drugs
and with other connective tissue disease like systemic
sclerosis and osteoarthritis were excluded.
Fasting blood samples were collected in EDTA vials
from the anticubital vein of the study group subjects and
processed immediately. Erythrocyte SOD activity was
measured by Marklund and Marklund’s method. The
enzyme SOD inhibits the auto-oxidation of pyrogallol by
catalysing the breakdown of superoxide. The inhibition of
pyrogallol oxidation by SOD is monitored at 420 nm and
the amount of enzyme producing 50 % inhibition is
defined as one unit of enzyme activity.8
Plasma ceruloplasmin levels were estimated by Ravins’s
method (1961). Ceruloplasmin due to its oxidase activity,
catalyses the oxidation of substrate p- phenylenediamine
chloride into purple coloured oxidation product,
measured spectrophotometrically at 530 nm.9
Erythrocyte glutathione peroxidase (GSHPx) activity was
estimated by Beutler’s method (1971), after preparation
of hemolysate. GSHPx catalyse the oxidation of reduced
glutathione (GSH) to oxidized glutathione (GSSG) by
H2O2. The rate of formation of GSSG is measured by
means of glutathione reductase reaction in which
NADPH is oxidized and measured at 340 nm.10
Erythrocyte catalase activity was estimated by Goth’s
method which involves the enzymatic breakdown of
H2O2 under optimized condition followed by
spectrophotometric assay of H2O2 (405 nm) based on
formation of its stable complex with ammonium
molybdate.11 Plasma CRP levels were measured using
commercially available ELISA kits (R&D Systems,
USA), according to manufacturer’s instructions.
Statistical analysis
The data collected from study group subjects were
entered separately in Microsoft Excel sheet of windows
2007 and values were expressed as Mean ± SD. The
significance of mean difference between study group
subjects was compared by using Student’s t test. The
distribution of t-probability was calculated depending on
n and significance of test was obtained. P value <0.05
and <0.001 were considered as significant and highly
significant respectively.
RESULTS
The level of antioxidant enzymes and systemic
inflammation in active RA patients and controls were
depicted in Table 1. In the present study, erythrocyte
SOD and GSHPx levels were significantly decreased in
patients with active RA (P <0.001; 42.27% low and P
Saxena R et al. Int J Res Orthop. 2015 Dec;1(1):7-10
International Journal of Research in Orthopaedics | October-December 2015 | Vol 1 | Issue 1 Page 9
<0.05; 43.5% low respectively) as compared to controls.
Plasma Catalase activity was also significantly low in
active RA patients (P<0.001; 45.52% low) whereas
plasma ceruloplasmin level was significantly elevated in
active RA subjects as compared to controls (P<0.001;
30.65% high). Plasma CRP levels were found to be
significantly high (P<0.001; 33.53% high) in patient
group as compared to healthy controls which reflect the
role of inflammation and oxidative stress in disease
process.
Table 1: Marker of systemic inflammation and antioxidant enzymes in study group subjects (Mean ± SD).
Particulars
Control Group (n=30)
Patient group (n=30)
%
Increase
%
Decrease
CRP (mg/L)
3.28 ± 0.14
4.38 ± 0.15
33.53 %
SOD
(U/gm Hb)
1932.24
231.53
1115.48
315.36
-
42.27
Ceruloplasmin
(mg %)
24.57 4.6
32.10 6.2
30.65
-
GSHPx
(IU/ gm Hb)
30.8 4.7
17.4 3.2
-
43.5
Catalase
(KU/L)
52.5 16.2
28.6 5.8
-
45.52
Where, *p<0.1: Non-significant; **p<0.05: Significant; **p<0.001: Highly significant
DISCUSSION
Reactive oxygen species have been implicated in the
pathogenesis of many disease processes including
rheumatological disorders.12 Superoxide anion, which is
believed to be one of the initiators of free radical
mediated pathological alterations (such as cartilage
degradation, synovitis and lipid peroxidation) leading to
arthritic complication, is efficiently removed by
antioxidant enzyme SOD.1 In the present study, we
observed that the SOD activity in active RA patients was
significantly low (P<0.001) as compared to healthy
controls, which direct towards its protective and
superoxide radical scavenging action in active RA
patients. Our findings were in concordance with the
findings of Karatas et al. According to them, reduced
activity of SOD could be the result of inter and
intramolecular cross-linking of proteins and thereby
causing conformational changes in SOD which leads to
accumulation of H2O2 followed by induction of lipid
peroxidation leading disease progression.13
Superoxide anion (O2.-) scavenging action of SOD can be
mimicked by other copper containing enzyme
ceruloplasmin also has the capacity to scavenge O2.-. In
the present study, plasma ceruloplasmin level was found
to be significantly increased (P<0.001) in active RA
patients as compared to healthy controls which indicate
that high ceruloplasmin level is associated with its
antioxidant activity to protect the myocardial tissue
against the deleterious effects of oxygen free radical and
to compensate the loss of SOD activity, occur due to
oxidative stress in RA patients.14 Among the enzymatic
systems of protecting the cell against free radical injury,
GSHPx and CAT play a crucial role in the final
detoxication of H2O2 to H2O. In the present study, low
GSHPx and CAT activity were observed (i.e. p<0.05 and
p<0.001 respectively) in active RA patients as compared
to controls. Aryaeian et al. also observed a direct
relationship of free radical production with active RA
progression and concluded that reduced level of CAT and
SOD may be due to their consumption during metabolism
of oxygen free radicals. However, it is unclear whether
the reduced activity of antioxidant enzymes is the cause
or the consequence of the increased oxidative stress in
RA.15
Moreover, reactive oxygen species and their
intermediates serve as mediators of inflammation in
inflammatory and arthritic disorders by enhancing
various culprit events such as inhibition of glycolytic
enzymes, reduction of antioxidant reserves in synovial
fluid and activation of proteolytic enzymes to degrade
cartilage. 6 In the present study, plasma CRP levels were
found to be significantly high (p<0.001) in active RA
patient which clarify the combined role of inflammation
and oxidative stress in the etiopathogenesis of active RA
and its complications.7,14,16
On the basis of present findings and consistent findings
of previous studies, it can be inferred that these
antioxidant enzymes and CRP are excellent markers of
oxidative stress and systemic inflammation in active RA
patients. It also authenticate the fact that combined effect
of inflammation and oxidative stress plays a significant
role in the etiopathogenesis of RA and the patients are
unable to counteract the augmented oxidative stress
effectively. Thus, antioxidant supplementation in
diet/drug regime regularly along with anti-inflammatory
drug as prescribed by physician may reduce the RA
progression and its complications.
Saxena R et al. Int J Res Orthop. 2015 Dec;1(1):7-10
International Journal of Research in Orthopaedics | October-December 2015 | Vol 1 | Issue 1 Page 10
ACKNOWLEDGEMENTS
We are thankful to entire Department of Orthopedics for
active participation and co-operation in the study. All the
authors have equally contributed.
Funding: No funding sources
Conflict of interest: None declared
Ethical approval: The study was approved by the
Institutional Ethics Committee
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Cite this article as: Saxena R, Suneja S, Saxena R,
Sharma D, Milton Lal A. Cumulative effect of
systemic inflammation and oxidative stress in 40
known cases of active rheumatoid arthritis. Int J Res
Orthop 2015;1:7-10.
... Malondialdehyde is the major lipid peroxidation product which is mostly used to assess the extent of inflammation and oxidative stress [62,63]. Thus in the present study, above results indicate the activation of MPO and NOS in CIA rats generate more reactive oxygen species (ROS) leading to oxidative stress in rheumatoid arthritis. ...
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