Research Article

The effect of progesterone on systemic inflammation and

oxidative stress in the rat model of sepsis
Ayse Nur Aksoy, Aysun Toker1, Muhammet Celk2, Mehmet Aksoy3, Zekai Halc4, Hulya Aksoy5

ABSTRACT
Objectives: To explore the protective effect of progesterone on inflammation and
oxidative stress in a rat model of sepsis created by cecal ligation and puncture (CLP).
Department of Obsterics and
Materials and Methods: Rats were randomly divided into 4 groups: Overiectomy
Gynecology, Nenehatun Hospital,
Erzurum, 1Department of group (OVX), sham operated (control), sepsis (CLP) group and progesterone-treated
Biochemistry, Meram Faculty of CLP group (CLP+ progesterone). The rats in CLP+ progesterone group received
Medicine, Konya University, Konya, intraperitoneal progesterone (2 mg/kg). Cardiac blood samples were obtained for
2
Department of Biochemistry, the measurement levels of interleukin-6 (IL-6) and tumor necrosis factor- (TNF-).
Goverment Hospital of Oltu, Tissue samples, including liver, kidney and uterus of rats were prepared to determine
3
Departments of Anesthesiology activities of myeloperoxidase (MPO), glutathione peroxidase (GPx) and levels of
and Reanimation, 4Pharmacology, malondialdehyde (MDA). Results: Increased serum IL-6 and TNF- levels were found in
5
Biochemistry, Faculty of Medicine,
the CLP group in comparison with the control group (P = 0.01, P = 0.02; respectively). In
Atatrk University, Erzurum, Turkey
CLP+ progesterone group, mean MDA concentration of kidney tissue was significantly
Submission: 02-11-2013 lower than in CLP group (P = 0.003). Liver MDA concentration of the CLP+ progesterone
Revised: 24-03-2014 group was not significantly different from that of the control group. While there were
Accepted: 25-09-2014 no significant differences among groups regarding liver MPO; in the CLP group, MPO
activity in kidney (P = 0.02) and uterine tissues (P = 0.03) were found to be significantly
Correspondence to: higher compared to the control group. In CLP+ progesterone group, mean MPO
Dr. Ayse Nur Aksoy, activities of all tissues were not different than those of control group. The uterine
E-mail: draysenuraksoy tissue GPx activity in the CLP+ progesterone group was not statistically significantly
@hotmail.com different from control group. Conclusions: We suggest that progesterone ameliorates
sepsis syndrome by reduction of the inflammatory cytokines IL-6 and TNF-, and by
restoration of antioxidant enzyme activities in some tissues.

KEY WORDS: Inflammation, oxidative stress, progesterone, sepsis

Introduction There is inflammatory response in the pathogenesis

Sepsis is defined as the systemic response to infection,
and it has a complex pathophysiology.[1] While severe sepsis
is manifested by organ dysfunction, septic shock is a type of
severe sepsis marked by hypotension despite fluid resuscitation.
However, although there are many different therapeutic
modalities; severe sepsis and septic shock are major causes
of mortality in intensive care units.[2,3]
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DOI: 10.4103/0253-7613.144922
of sepsis and associated with excessive production of
cytokines such as interleukin-6 (IL-6) and tumor necrosis
factor- (TNF-). TNF- plays a pivotal role in the
pathogenesis of an early phase of shock.[4,5] The endothelial
cells and neutrophils were activated with TNF- to induce
an inflammatory response. Additionally, expression of
adhesion molecules increases on neutrophils. Activated
neutrophils damage tissues by releasing oxygen-free radicals
and proteases. In addition, TNF- amplifies inflammatory
cascades by activating macrophages/monocytes to secrete
other pro-inflammatory cytokines. These cytokines cause
tissue damage and contribute to apoptosis.[6,7]
While the effect of progesterone on cecal ligation and
puncture (CLP)-induced tissue injury has not been studied,
progesterone is reported to have a protective effect on cerebral
or myocardial I/R injury in rats.[8,9] In one study that was
conducted to examine the inhibitory effects of progesterone

622 Indian Journal of Pharmacology | December 2014 | Vol 46 | Issue 6

 Aksoy, et al.: Progesterone in sepsis
on inflammatory response, progesterone treatment decreased
expression of inflammatory cytokines e.g., IL-1 and TNF- in
brain-injured rats.[8] Progesterone also may reduce oxidative
stress by its membrane-stabilizing effect.[10]
The aim of this study was investigate whether progesterone
affect systemic inflammation and tissue damage in female rat
sepsis models of polymicrobial peritonitis caused by CLP.
Materials and Methods
Experimental Animals
This study was performed in accordance with the National
Institute of Healths approved guidelines and the experimental
protocol (protocol number: B.30.2.ATA.023.85-59) approved by
the Animal Research Ethics Committee of Ataturk University,
Medical Faculty, Erzurum, Turkey.
Twenty-eight adult female Sprague-Dawley rats (weighing
200-250 g) were purchased from the Ataturk University
Experimental Animal Laboratory. All rats were kept in a
light- and temperature-controlled room with 14:10-hour
light-dark cycles and temperature of 22 0.5C, and were fed
a standard pellet diet. Fifteen days before the experimental
study, all rats were bilaterally ovariectomized to eliminate
endogenous progesterone production and to reduce systemic
ovarian hormone levels. Surgical anesthesia was provided
intraperitoneally (i.p.) Thiopental dose of 25 mg/kg was
administered and bilateral ovariectomy was performed by a
midline dorsal skin incision. The peritoneal cavity was reached
and ovaries were found. After the ligation of blood vessels, the
connection fallopian tube and uterine horn was cut and ovaries
were excised. Then the skin incision was closed using a 4/0
sterile synthetic absorbable suture. Surgical procedure was
carried out under highly aseptic conditions.
Animal Groups and Study Design
The rats were randomly divided into four groups of
seven individuals: The overiectomy group (OVX), the sham
operated (control) group, the sepsis (CLP) group and the
progesterone-treated CLP group (CLP+ progesterone). A CLP
method of polymicrobial sepsis was applied to the rats in
CLP and CLP+ progesterone groups. Polymicrobial sepsis
was induced by cecal ligation and two-hole puncture, as
described by Wichterman et al.,[11] with minor modifications.
Thiopental (25 mg/kg) was used to provide surgical anesthesia
in rats. After shaving the rats abdomen, a midline laparotomy
was performed and the cecum was ligated just below the
ileocecal valve using 3-0 silk ligatures. Using a 12-gauge
needle, the cecum was perforated through the cecum distal to
the point of ligation at two locations 1 cm apart. The cecum
was then returned to the abdomen and the abdominal incision
was closed using a 4/0 sterile synthetic absorbable suture.
The wound was bathed in a 1% lidocaine solution to provide
analgesia. Laparotomy was performed on the control group, and
the cecum was manipulated, although not ligated or perforated.
All animals were resuscitated with normal saline (2 mL/100 g
body weight) injected subcutaneously at the time of surgery
and also at 6 hours postoperatively. Rats of CLP+ progesterone
group received i.p. injections of 2 mg/kg progesterone in
peanut oil at 2 hours after sepsis induction. Sham-operated
rats served as controls. Peanut oil was used as a vehicle and
administered by i.p. route to the control group. Postoperatively,
the rats were deprived of food, although they had free access
to water until they were sacrificed. Sixteen hours after the
surgery, all rats were sacrificed with an overdose of a general
anesthetic (thiopental sodium, 50 mg/kg).
Cardiac blood samples were obtained for measurement of
the levels of TNF- and IL-6. Serum samples were aliqouted
and stored at 80C until the analysis date. The liver,
uterus and kidney tissues of all rats were rapidly removed
and washed in ice-cold saline. The organs were labeled
and stored at 80C until the biochemical analyses were
conducted. Activities of myeloperoxidase (MPO), indicating
neutrophil infiltration, and glutathione peroxidase (GPx),
which is an antioxidant enzyme, and concentration of
malondialdehyde (MDA), a marker of lipid peroxidation, were
measured in tissue samples.
Preparation of Tissues
A portion of tissue was homogenized in a potassium
phosphate buffer (pH: 6) containing 5% hexadecyltrimethyl
ammonium bromide solution (w/v) for MPO activity
measurement; the rest of the tissue was homogenized using
a solution of 1.15% KCl for GPx and MDA measurements. The
homogenates were centrifuged at 8000xg, +4C for 15 minutes.
Supernatants were then used for biochemical analysis.
Biochemical Analyses
Serum TNF- and IL-6 levels
Serum TNF- and IL-6 levels were measured using rat TNF-
ELISA kit (Invitrogen, Carlsbad, CA, USA; catalog number:
KRC3011, lot number: 776995A) and rat IL-6 Platinum ELISA
kit (eBioscience, San Diego, CA, USA; catalog number: BMS625,
lot number: 60405021) according to the manufacturers
instructions. Intra-assay coefficiency of variation (CV) was 5.8%
for TNF- and 5% for IL-6. Inter-assay CV was 8.3% for TNF-
and 9% for IL-6. Results were expressed as pg/ml.
MPO activity
MPO activity was measured according to Bradley et al.s
modified method.[12] It was determined by adding 100 L of the
supernatant to 1.9 mL of 10 mmol/L phosphate buffer (PH = 6.0)
and 1 mL of 1.5 mmol/L o-dianisidine hydrochloride containing
0.0005% (wt/vol) hydrogen peroxide. The changes in each
samples absorbance at 450 nm were recorded on a UVvis
spectrophotometer. MPO activity was expressed as U/g protein.
GPx activity
GPx activity was measured according to the method
described by Paglia and Valentine.[13] GPx in tissue catalyzed
the oxidation of glutathione by hydrogen hydroperoxide. Then,
in the presence of glutathione reductase and nicotinamide
adenine dinucleotide phosphate, the oxidized glutathione was
converted to its reduced form with a concomitant oxidation
of the reduced form of nicotinamide adenine dinucleotide
phosphate to nicotinamide adenine dinucleotide phosphate. The
decrease in absorbance was measured at 340 nm. GPx activity
was expressed as U/g protein.
MDA levels
Tissue MDA levels were determined spectrophotometrically
according to the method described by Ohkawa et al.[14] Briefly,
supernatant (0.5 ml) was added to a solution containing
Indian Journal of Pharmacology | December 2014 | Vol 46 | Issue 6 623
 Aksoy, et al.: Progesterone in sepsis

0.2 mL of 80 g/L sodium lauryl sulfate, 1.5 mL of 200 g/L acetic
acid, 1.5 mL of 8 g/L 2-thiobarbiturate and 0.3 mL distilled
water. The mixture was incubated at boiled water for 1 h.
Upon cooling, 5 mL of n-butanol: Pyridine (15:l) was added.
The mixture was vortexed and centrifuged. The absorbance of
the supernatant was measured at 532 nm. The standard curve
was obtained by using 1,1,3,3-tetramethoxypropane. Results
were expressed as mol/g protein.
Statistical Analysis
Statistical analysis was carried out with a statistical
software package (SPSS 17.0). Results were given as
mean SD. Differences among groups were tested using
the ANOVA post hoc LSD test. Significance was considered
as P < 0.05.
Results
Increased plasma IL-6 and TNF- levels (pg/ml) were
found in the CLP group (36.17 3.41 and 15.56 4.46)
in comparison with the control group (26.85 2.74 and
11.5 1.72) (P = 0.01, P = 0.02; respectively). However
in CLP+ progesterone group, the serum levels of IL-6 and
TNF- (31.79 7.89 and 12.99 3.42) were similar to the
control group [Figure 1]. MPO, GPx activities and MDA levels in
liver, kidney and uterine tissues of study groups are presented
in Table 1. In the OVX group, while liver and uterine MDA
concentrations (mol/g protein) were similar to control, the
kidney MDA concentration was higher than those of the control
group (P = 0.02). In the CLP group, kidney MDA concentration
was significantly higher than in the control (P = 0.0001) and
OVX groups (P = 0.02). In CLP+ progesterone group, mean
MDA concentration of kidney tissue was significantly lower
than in CLP group (P = 0.003). MDA concentrations in the
liver and uterine tissues were significantly elevated in the CLP
group compared to the control group (P = 0.01 for both). Liver
MDA concentration of the CLP+ progesterone group was not
significantly different from that of control group. While there
were no significant differences among groups regarding to
liver MPO (U/g protein); in the CLP group, MPO activity in
kidney (P = 0.02) and uterine tissue (P = 0.03) were found
to be significantly higher compared to the control group. In
CLP+ progesterone group, mean MPO activities of all tissues
were not different than those of control group. While the GPx
activity (U/g protein) in uterine tissue of the CLP group was
lower than those of the control group (P = 0.02), the GPx
activity in the CLP+ progesterone group was not statistically
significantly different from control group. In the kidney and
liver tissues, there were no significant differences regarding
GPx activity among groups.
Discussion
Oxidative stress is important in sepsis. [15] Excessive
production of cytokines (e.g., IL-6, TNF-) is reported in a part
of sepsis pathogenesis.[16,17] The mortality and morbidity of
sepsis are high despite advances in new therapeutic agents.
Considering that sepsis is a very significant disease that leads
to death in intensive care units, there is a great need to better
understand the pathogenesis of this disease and develop
effective treatment modalities. The purpose of this study was to
examine the effects of progesterone on systemic inflammation
and tissue damage of ovariectomized rats in a CLP-induced
sepsis model.
Progesterone, a sex steroid hormone has been reported to
suppress the oxidative damage in cardiac and brain tissues,[8,9]
decrease oxidative damage in the colonic mucosa [18] and
reduce cell apoptosis in brain tissue.[19] However, the potential
role of progesterone in sepsis has not been studied. In our
study, increased serum levels of IL-6 and TNF- reduced after
progesterone treatment in a rat model created sepsis with CLP.
Also, CLP increased the MPO activity in kidney and uterine
tissues, but similar values to the control group were observed
after treatment with progesterone. The key finding in our study
was that exogenously given progesterone in sepsis resulted in a
significant decrease in systemic inflammation and MPO activity,
as a leukocyte activation marker, compared to rats that did
not receive it. Emerging evidence suggests that progesterone
has the potential to influence inflammation.[20,21] In a study,
expression of TNF- reduced in progesterone-treated rats
compared to controls and authors suggested that progesterone
Table 1:

Figure 1: Comparison of groups according to serum TNF alpha and MPO and GPx activities and MDA levels in liver, kidney and
IL-6 levels. *P = 0.01 and **P = 0.02 compared to control group uterine tissues of control, CLP, OVX and CLP+Prog groups

Control CLP OVX CLP+Prog

Liver MDA 7.863.83 15.45.97a 11.43.60 10.66.22
Kidney MDA 3.062.80 35.416.6b,d 19.016.4c 14.166.21e
Uterine MDA 1.110.87 2.861.56a 2.091.02 2.381.07
Liver MPO 1.060.33 1.500.85 1.140.45 1.170.44
Kidney MPO 1.060.88 2.832.09c 2.030.85 2.170.93
Uterine MPO 5.183.00 15.512.5f 6.467.44 10.46.86
Liver GPx 2.991.02 3.322.33 1.700.67 1.410.92
Kidney GPx 1.943.36 4.972.83 5.174.01 0.470.44
Uterine GPx 2.701.27 1.530.72c 2.140.91 2.020.56
Results were presented as meanstandard deviation. aP=0.01, bP=0.0001, cP=0.02
and fP=0.03 compared with control group; dP=0.02 compared with OVX group;
e
P=0.003 compared with CLP group. MDA (malondialdehyde) levels were expressed
as mol/g protein; MPO (myeloperoxidase) and GPx (glutathione peroxidase)
activities were expressed as U/g protein; Control: Sham operated group,
CLP: Sepsis group, OVX: Overiectomy group and CLP+progesterone: Progesterone-
treated CLP group

624 Indian Journal of Pharmacology | December 2014 | Vol 46 | Issue 6

 Aksoy, et al.: Progesterone in sepsis
administration is beneficial for cerebral trauma and infarction
by inhibiting inflammatory reaction.[8] Additionally, in Dhote
et al.s study,[9] they investigated the effect of progesterone
on oxidative stress and myocardial ischemia markers in the
myocardial ischemia-reperfusion model. At the end of the
study, MPO activity was reduced after progesterone treatment
in female rats. They concluded that the administration of
progesterone during myocardial injury reduces inflammatory
reactivity and provides better cardioprotection in female rats
compared to male and they suggested that progesterone
therapy may be useful in myocardial injury due to a diminished
inflammatory response.
There is no consensus among researchers regarding the
influence of gender on survival in patients with sepsis. For
example, Esper et al.[22] found no gender differences, Adrie
et al.[23] reported higher risk in men and Dombrovskiy et al.[24]
declared higher risk in women in terms of sepsis survival. On
the other hand, Schroder et al.[25] suggested that sex hormones
estrogen and progesterone may be effective in providing
protection against sepsis in women. Before beginning the
experimental study, we removed the ovaries of all rats to
eliminate endogenous progesterone production and to reduce
systemic ovarian hormone levels. Our results demonstrated
that progesterone attenuates the sepsis-induced elevations
of IL-6 and TNF- . We applied 2 mg/kg dose of progesterone
immediately after CLP. In the brain injury model, it was suggested
that progesterone in inhibiting the proinflammatory cytokines is
time-dependent.[26] Progesterone effectively reduced the gene
expression of IL-1 and TNF- at 3 hours post-injury. After 8
and 12 hours of continued administration of progesterone,
cytokine elevations were not observed. Therefore, we selected
the progesterone delivery time according to this data. It has
been demonstrated that progesterone is also neuroprotective
in cerebral ischemia and traumatic brain injury.[10,26] Zhao
et al.[27] researched the effects of progesterone on the intestinal
pathophysiologic changes following subarachnoid hemorrhage
in male rats. After progesterone administration (2 mg/kg i.p.),
the concentrations of IL-1, TNF- and IL-6 were found to
be significantly lower in rat ileum tissue. They found that
progesterone administration modulates intestinal inflammatory
response. Used dose of progesterone in this current study was
selected based on this study.[27]
Researchers have examined the effect of different agents
in the treatment of sepsis.[16,17,28] Sahin et al.[28] examined the
effect of carnosine in an experimental septic shock model.
They concluded that carnosine may be an effective treatment
for oxidative damage in cases of septic shock. According to
our literature data, this present study is the first investigating
the efficacy of progesterone on sepsis in a rat model created
sepsis using CLP.
MDA is a lipid peroxidation product and a marker
for tissue damage.[29] In a recent study, Karatepe et al.[18]
researched the effects of progesterone on an experimental
colitis model. They reported both lower blood and colonic
tissue levels of MDA, IL-6 and TNF- in rats treated with
progesterone (subcutaneously with dose of 2 mg/kg)
compared to the rats that only created colitis by intrarectal
administration of 5 mg trinitrobenzene sulfonic acid. In
another study,[30] investigating possible neuroprotective effects
of progesterone in rats subjected to global cerebral ischemia,
progesterone administration ameliorated ischemia-induced
decrease in glutathione (major endogenous antioxidant)
and increase in MDA levels in hippocampus, striatum and
cortex. They evaluated the remarkable neuroprotective effect
of progesterone reducing oxidative stress. In our study, the
MDA concentration in tissues of uterine, liver and kidney and
plasma IL-6 and TNF- level increased in rats after created
CLP, but the values after progesterone treatment were similar
to the values in the control group. Also while increased uterine
tissue GPx activity (an enzymatic antioxidant) was found
in rats to create sepsis, similar uterine GPx activity to the
control group was observed after progesterone treatment in
this current study.
Conclusion
It may be suggested that progesterone ameliorates sepsis
syndrome by reduction of the inflammatory cytokines, IL-6
and TNF-, and by restoration of antioxidant defense system.
Progesterone therefore may be beneficial in controlling
inflammation in sepsis. Further prospective and randomized
clinical controlled trials are required to investigate the
therapeutic role of progesterone in tissue damage resulting
from sepsis.
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Cite this article as: Aksoy AN, Toker A, Celik M, Aksoy M, Halici Z, Aksoy H.
The effect of progesterone on systemic inflammation and oxidative stress in
the rat model of sepsis. Indian J Pharmacol 2014;46:622-6.
Source of Support: Nil. Conflict of Interest: No.
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