Resolvins RvD1 and 17(R)-RvD1

alleviate signs of inflammation

in a rat model of endometriosis
Natalia Dmitrieva, Ph.D., Gregory Suess, B.S., and Russell Shirley, B.S.
Program in Neuroscience, Florida State University, Tallahassee, Florida

Objective: To study the effects of two resolvins of D series, RvD1 and 17(R)-RvD1, on inflammatory signs associated with endometri-
osis (ENDO).
Design: In vivo research study.
Setting: Research laboratory.
Animal(s): Female Sprague-Dawley rats.
Intervention(s): Intravenous or intraperitoneal injections of RvD1 (300 ng/kg) or 17(R)-RvD1 (300 and 900 ng/kg) in rats with surgi-
cally induced ENDO.
Main Outcome Measure(s): Vascular permeability of ectopic endometrial growths was assessed by Evans Blue extravasation; vaginal
hyperalgesia was assessed with telemetered visceromotor response.
Result(s): Both resolvins, but not vehicle, significantly decreased vascular permeability in ectopic endometrial tissue. 17(R)-RvD1 also
significantly alleviated severity of vaginal hyperalgesia.
Conclusion(s): Our results suggest that RvD1 and 17(R)-RvD1 can be considered for further
investigation of their therapeutic potential for treating ENDO. (Fertil SterilÒ 2014;102:
1191–6. Ó2014 by American Society for Reproductive Medicine.) Use your smartphone
Key Words: Proresolving lipid mediator, docosahexaenoic acid, omega-3 polyunsaturated fatty to scan this QR code
acid, cyclo-oxygenase 2, hyperalgesia, endometrium and connect to the
discussion forum for
this article now.*
Discuss: You can discuss this article with its authors and with other ASRM members at http://
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sympathetic fibers (15–17). Similar

E
ndometriosis (ENDO) is a (8). Similar to women, rats with ENDO
common chronic, estrogen- exhibit abnormal sensitivity in the pel- to other inflammatory conditions,
dependent, painful condition vic area (i.e., vaginal hyperalgesia [9] vessel permeability to blood proteins
(1–3). The incidence of ENDO is that can be assessed with the viscero- in endometrial growths in women
estimated to be approximately 7% but motor response [VMR]) (10, 11). (14, 18) and rats (17, 19) is signifi-
can be as high as 10%–15% among Evidence from human and animal cantly increased. Ectopic endometrial
women of reproductive age (1, 4–6). studies suggests that abnormal im- tissue produces inflammatory prost-
Women with ENDO often experience mune, vascular, and neural activities aglandins, cytokines, and growth
dysmenorrhea (excessive menstrual in ectopic endometrium contribute to factors (17, 20–24). Most of these
pain), dyspareunia (vaginal hyper- inflammatory signs and symptoms inflammatory mediators facilitate
algesia), dyschezia (pain with associated with ENDO. Ectopic endo- plasma protein extravasation into
defecation), and chronic pelvic pain, metrial growths in women and rats surrounding tissue (25–31) that can
which can co-occur with a range of become highly vascularized, infiltrated activate visceral nociceptors (26, 32–
other painful conditions (7). Symptoms with polymorphonuclear cells and 34). The resultant neural activity (35,
can range from moderate to severe. A activated macrophages (12–14), and 36) further exacerbates blood vessel
rat model of ENDO has been developed densely innervated with sensory and leakage. In rats with ENDO, this
Received March 31, 2014; revised and accepted June 30, 2014; published online August 11, 2014.
neurogenic component of plasma
N.D. has nothing to disclose. G.S. has nothing to disclose. R.S. has nothing to disclose. protein extravasation was found to
This research was partially funded by Bayer HealthCare Pharmaceuticals (Grant4Tagerts). become significant in the early stages
Reprint requests: Natalia Dmitrieva, Ph.D., Program in Neuroscience/Psychology, Florida State Univer-
sity, 1107 West Call St., Tallahassee, Florida 32306-4301 (E-mail: dmitrieva@psy.fsu.edu). of cyst development (19). Activated
nociceptors are known to contribute
Fertility and Sterility® Vol. 102, No. 4, October 2014 0015-0282/$36.00
Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc.
to increased sensory sensitivity,
http://dx.doi.org/10.1016/j.fertnstert.2014.06.046 including pain (37, 38).

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ORIGINAL ARTICLE: REPRODUCTIVE SCIENCE

Resolvins (an acronym of ‘‘resolution phase interaction
products’’) are proresolving lipid mediators that received their
name for their distinctive role in resolution of acute immune
inflammatory response (down-regulation of leucocyte
infiltration, facilitation of phagocytotic activity, and
apoptotic cell removal) (39). Resolvins are biosynthesized
from omega-3 polyunsaturated fatty acids by 5- and
15-lipoxygenases and cyclo-oxygenase 2 (COX2), enzymes
that are well known for their roles in production of proinflam-
matory lipids. Resolvin RvD1 [17(S)-resolvin D1] is produced
from docosahexaenoic acid in the site of inflammation by leu-
kocytes and endothelial cells (40, 41). Biosynthesis of RvD1
requires 5- and 15-lipoxygenases, whereas the final step in
production of its stable analog 17(R)-RvD1 requires aspirin-
acetylated COX2 (41). Recent studies in animal models
demonstrated the effectiveness of low doses of RvD1 and
17(R)-RvD1 in reducing inflammatory signs, including pain
and edema (42–45). To produce its peripheral effects, RvD1
activates two high-affinity G protein–coupled receptors ex-
pressed in peripheral leukocytes, macrophages, and endothe-
lial cells, namely ALX/FPP2 and CPR32 (46, 47). The existence
of spinal sites of RvD1 actions has been also suggested (45).
Resolvins can produce anti-inflammatory actions at doses
at least 10–100 times lower than opioids and COX2 inhibitors
without adverse effects (42, 43, 45, 48, 49). Experimental
findings suggest that resolvins can effectively alleviate some
chronic inflammatory signs. Thus, 17(R)-RvD1 and its
precursor have alleviated chronic inflammatory signs and
abnormal sensory sensitivity in a mouse model of arthritis
(43). Together this information suggests that RvD1 and
17(R)-RvD1 have the potential to alleviate inflammatory
signs associated with ENDO. If so, these resolvins should
reduce plasma protein extravasation in ectopic growths and
alleviate ENDO-induced vaginal hyperalgesia.
MATERIALS AND METHODS
This study was approved by the Florida State University An-
imal Care and Use Committee (protocol #1239).
Subjects
Female Sprague-Dawley rats were used. Estrous cycle was
determined daily by cytologic examination of vaginal lavage
collected approximately 2 hours after lights on (50). All ex-
periments were done 10–12 weeks after ENDO surgery.
Endometriosis Surgeries
Endometriosis surgeries were performed under ketamine/xyla-
zine anesthesia (73/8.8 mg/kg intraperitoneal [IP]) as previously
described (51). Briefly, the rat was kept warm on a heating pad.
A small incision was made in the middle of the abdomen. An
approximately 1-cm segment of the middle part of one uterine
horn was clamped and excised. Four 2 mm
2 mm pieces of the
excised uterine tissue were sutured on alternate mesenteric
cascade arteries. Muscle and skin were sutured separately. Bu-
pivacaine was given locally and butorphanol SC immediately
after surgery to alleviate postoperative pain.
RvD1 and 17(R)-RvD1 Treatments for Evans Blue
Assessment
All rats were in proestrus on the day of the experiment. Rats
were first anesthetized with urethane (1.2 g/kg) and placed
on a warm heating pad. The jugular vein was exposed through
an incision and catheterized; the skin was sutured.
Rats in one group received an injection through the jugu-
lar catheter of a single dose of RvD1 (300 ng/kg in 0.15 mL of
phosphate-buffered saline [PBS]), which was flushed through
with 0.1 mL heparinized saline. Rats in another group were in-
jected via the jugular catheter with a similar volume of PBS.
Three hours later, Evans Blue (EB) was injected.
Rats in three other groups were injected (IP) with one of
two doses of a stable analog 17(R)-RvD1 (300 or 900 ng/kg
in 0.15 mL of PBS) or PBS. Evans Blue was injected via the ju-
gular vein 3 hours later.
Evans Blue dye extravasation in ectopic growths, which
measures vascular permeability, was used as an indirect
assessment of neurogenic, mainly C-fiber activity (35). Evans
Blue (50 mg/kg in saline) was delivered through the catheter.
Thirty minutes later, excess dye was rinsed out of blood ves-
sels by delivering approximately 200 mL of saline through the
catheter. Cysts were harvested, weighed, and incubated in
formamide at 60 C for 48 hours. Optical density of the sample
and standard solutions was measured spectrophotometrically
(l ¼ 620 nm). The amount of EB extracted from each sample
was calculated as milligrams of EB per gram of tissue.
The differences between the RvD1- and vehicle-treated
groups were analyzed with Student's t test, and between
17(R)-RvD1 and vehicle with analysis of variance (ANOVA)
followed by post hoc Dunnett tests, with significance set at
P%.05.
Telemetric Probe Implantation
Seven weeks after ENDO surgery, a telemetric probe
(TA11CTAF40; DSI) was implanted under aseptic conditions
and ketamine/xylazine anesthesia under the skin of the right
abdominal flank, as described by Dmitrieva et al. (51). Elec-
trodes were tunneled under the skin and implanted in the
left inguinal muscle. Experiments began approximately
7 days after implantation.
17(R)-RvD1 Treatment and Assessment of Vaginal
Nociception
17(R)-RvD1 treatment and assessment of vaginal nociception
in conscious ENDO rats (n ¼ 5) were based on telemetered
VMR to vaginal distention. The rat was loosely enclosed in
a transparent Plexiglas box. The box was placed on the
receiver. A small balloon (approximately 10-mm diameter
when fully inflated) connected to a pressure transducer was
inserted into the middle of the vaginal canal. After a
10-minute resting period, the balloon was inflated by an infu-
sion pump (0.3 mL/min, 1 mL maximum). Electrical activity
from the inguinal muscle was radio-relayed to the receiver,
synchronized with the signal from the pressure transducer,
and processed by a Ponemah Telemetry System (DSI).

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 Fertility and Sterility®

Electromyographic activity was recorded before and during
the time when the vaginal balloon was inflated.
The integral of the rectified electromyographic signal was
calculated in 100-ms intervals. The volume threshold of the
VMR activity 200% or higher than baseline was calculated
(11). Two to four baseline VMRs were recorded per each
estrous stage (metestrus, diestrus, proestrus, and estrus).
Average volume thresholds were calculated for each stage
for each rat.
Vehicle (PBS) was injected IP when the rat was in proes-
trus. The VMR was recorded 3–3.5 hours after injection.
17(R)-RvD1 (900 ng/kg IP) was injected on the next proestrus
day after vehicle. The VMR in some rats was also monitored in
proestrus 3–3.5 hours after this treatment.
Differences in VMR thresholds between baseline, vehicle,
and resolvin groups were analyzed by ANOVA, followed by
Tukey tests. Differences with P< .05 were considered
significant.
RESULTS
RvD1 or 17(R)-RvD1 Reduced Neurogenic Activity
in Ectopic Growths
We confirmed previously that the growth size rapidly in-
creases in the first 4–8 weeks after implantation (8) and pla-
teaus between 8 and 10 weeks and changes very little after
that (9). We also recently reported that EB extravasation in
rat endometrial growths becomes significantly elevated
beginning 4 weeks after ENDO surgery (19). In the present
study all experiments were done 10–12 weeks after ENDO sur-
gery, when the cyst size and cyst vascular permeability are
high and stable (19). Figure 1A shows that 300 ng/kg RvD1
but not vehicle delivered through the jugular vein signifi-
cantly decreased EB extravasation in growths (P< .05, paired
t test). The percent decrease by RvD1 treatment was 63.1%.
Both doses of a stable analog, 17(R)-RvD1 (300 and
900 ng/kg IP), significantly decreased the amounts of EB in
ectopic growths compared with vehicle (Fig. 1B; P< .05,
ANOVA). The percent changes produced by 300 and
900 ng/kg were 49% and 54.1%, respectively.
(R)-RvD1 Alleviated Vaginal Hyperalgesia
Severity of vaginal hyperalgesia in ENDO rats was monitored
across the estrous cycle as previously described (51). As found
in that study, here also the severity was highest in proestrus
(not shown). Therefore all treatments and VMR measurements
were done in proestrus. The outcomes from these experiments
were compared with the average of three to four baseline VMR
thresholds also measured in proestrus. Injecting vehicle alone
did not affect the VMR threshold, but treatment with 900 ng/
kg 17(R)-RvD1 increased the threshold significantly (Fig. 2A;
P< .05, ANOVA). The severity of vaginal hyperalgesia
decreased by 68.1% in rats treated with 17(R)-RvD1 compared
with vehicle (Fig. 2B). On the fourth day after the 17(R)-RvD1,
when the rat was in proestrus again, the VMR threshold was
still elevated in three of four rats; however, this increase
was not significant.
DISCUSSION
Our results showed that low doses of RvD1 delivered via the
jugular vein and its stable analog 17(R)-RvD1 injected IP
significantly decreased permeability of blood vessels in rat
endometrial cysts. 17(R)-RvD1 also alleviated vaginal hyper-
algesia induced by ENDO. The existing literature suggests that
mechanisms of resolvins' actions can be complex. Below we
summarize the reports that provide evidence of the mecha-
nisms activated by RvD1 and 17(R)-RvD1, which can also
lead to reduction of inflammatory signs associated with
ENDO. We also discuss how these two resolvins can down-
regulate inflammatory molecules that play key roles in ENDO.
Peripheral Mechanisms that Involve Leukocytes
and Sensory Afferents
The possibility that RvD1 and 17(R)-RvD1 produced a direct ef-
fect on the ectopic growths' vasculature is plausible because ex-
pressions of FPP2/ALX and GPR32 receptors have been shown
in polymorphonuclear and endothelial cells (40, 41). The
following findings suggest that the treatment with resolvins
here reduced the number of leukocytes that infiltrate cysts

FIGURE 1

140 RvD1 (i.v.) 140 Rt-RvD1 (i.p.)

120 120
EB (mg/g of tissue)
EB (mg/ of tissue)

100 100 *
80 80
*
60 60 **
40 * 40
20 20
0 0
Vehicle 300 ng/kg Vehicle 300 ng/kg 900 ng/kg
Effects of a single injection of RvD1 (A, IV) or Rt-RvD1 (B, IP) on EB extravasation in endometrial cysts. The inset in (A) shows one cyst from a rat treated
with vehicle (left) and another cyst from a rat treated with RvD1 (right). Note the presence of the dark blue dye in the cyst vascular bed of the vehicle-
treated rat; the color of the cyst treated with RvD1 is lighter because the level of the dye is lower. *P<.05, **P<.01 compared with vehicle.
Dmitrieva. Resolvins resolve signs of endometriosis. Fertil Steril 2014.

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ORIGINAL ARTICLE: REPRODUCTIVE SCIENCE

contribution of neurogenic extravasation to an increased

FIGURE 2
vascular permeability in ectopic growths (19). Because RvD1
and 17(R)-RvD1 delivered systemically in our study produced
Vehicle a significant vascular effect, whereas an intrathecal injection
of 17(R)-RvD1 significantly alleviated mechanical hypersensi-
EMG
1 mv

tivity but not edema of a carrageenan-inflamed paw in rats, as

shown by others (55), it is likely that resolvins of the D series
produce a peripheral vascular effect when delivered systemi-
100 cm of water

cally. Therefore, RvD1 and 17(R)-RvD1 can decrease vascular

Pressure

permeability by inhibiting direct vascular, immune, and pe-

ripheral neurogenic activities induced by ENDO.

Central Neuronal and Nonneuronal Mechanisms

Rt-RvD1 Another explanation for the reduction in severity of ENDO-
induced hyperalgesia by RvD1 and 17(R)-RvD1 is inhibition
EMG
1 mv

of sensory nerve fibers innervating the growths as well as inhi-

bition of sensory activity in the spinal cord. This suggestion is
supported by reports showing that intrathecal administration
100 cm of water

of RvD1or 17(R)-RvD1 attenuated postoperative and inflam-

Pressure

matory pain in animal models (55–57). The mechanisms of

the spinal effect can be suppression of either COX2 and
0.5 min transcriptional factor nuclear factor kB (NF-kB) protein and/
or messenger RNA (mRNA) expressions in DRGs and spinal
neurons, as suggested by the studies showing that analgesia
1.0
0.9
* produced by an At-RvD1 precursor in a rat model of
0.8 adjuvant-induced arthritis correlates with the reduction in pro-
VMR threshold (ml)

0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Baseline Vehicle Rt-RvD1
Effect of a single IP injection of 900 ng/kg Rt-RvD1 on severity of
vaginal hyperalgesia. (A) Individual records of VMR response (upper
trace of each panel) to vaginal distention (lower trace of each
panel) of one rat after vehicle and Rt-RvD1. Arrowheads indicate
the VMR threshold. (B) Average VMR threshold measured after
vehicle, Rt-RvD1, and 4 to 5 days after treatment (on the next
proestrous day after treatment). *P<.05 compared with vehicle or
baseline.
Dmitrieva. Resolvins resolve signs of endometriosis. Fertil Steril 2014.
and that these cells produce less inflammatory mediators: RvD1
suppressed production of vascular adhesion molecule-1 and
vasoactive inflammatory mediators, such as tumor necrosis
factor (TNF)-a and prostaglandin E2, in stimulated choroid-
retinal endothelial cells (52); resolvins of the D series derivative
of docosahexaenoic acid, including RvD1 and 17(R)-RvD1,
have dose-dependently limited polymorphonuclear neutro-
phils migration across the endothelial layer in vitro and in-
hibited polymorphonuclear neutrophils infiltration in the site
of inflammation in vivo (41, 53, 54). A possibility of a
GPR32-mediated activation of sensory afferents in cysts also
exists because RvD1 attenuated an increase in intracellular
Ca2þ in response to activation of the thermo-transient receptor
potential channel in mouse dorsal root ganglia (DRG) neu-
rons (48). We have previously demonstrated a significant
tein and mRNA levels of these mediators in the spinal cord and
DRGs. A possible nonneuronal resolvin action was recently re-
ported by Abdelmoaty et al. (55): intrathecal-delivered 17(R)-
RvD1 significantly reduced the TNF level induced by paw
inflammation in the cerebrospinal fluid, possibly by blocking
its production in astrocytes. 17(R)-RvD1 in this study also
decreased TNF-induced Erk phosphorylation in astrocytes.
post Rt-RvD1 Altogether these data suggest that spinal mechanisms underly-
ing analgesic effects of resolvins can result from activation of
multiple neuronal and nonneuronal pathways.
Molecular Mechanisms that Regulate Key
Inflammatory Molecules
Evidence suggests that resolvins of the D series can down-
regulate activities of COX2 and NF-kB. Studies showing an
increased DNA-binding activity of NF-kB in red endometrial
lesions in women (58) and significant inhibition of prolifera-
tion and endometrial growth development in mice treated
with NF-kB blockers (59) suggest that the constitutive activity
of this transcriptional factor influences endometrial growth
development. Cyclo-oxygenase 2 plays an important role in
ENDO pathology (60). The mRNA and protein levels of
COX2 are significantly elevated in the ectopic endometrium
compared with the eutopic endometrium (60–62). The COX2
enzymatic product prostaglandin E2 can stimulate
aromatase activity in endometrial stromal and epithelial
cells, thereby maintaining a high level of local estrogen,
which is essential for growth and maintenance of
endometrial lesions (63, 64). Inhibition of COX2, on the
other hand, helped to suppress ectopic growth development
and improve fertility in murine models (65–68).

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Additionally, our recent findings showing a decrease in
severity of vaginal hyperalgesia by indomethacin in rats
with ENDO (51) emphasize the contribution of COX2 in
abnormal visceral sensory processing associated with
ENDO. Because RvD1 can suppress both NF-kB nuclear trans-
location and DNA binding (69), and an NF-kB inhibitor can
decrease the COX2 mRNA and protein levels as shown in
TNF-a–stimulated adenomyotic cells (70), it is possible that
RvD1 and 17(R)-RvD1 provide a negative feedback to
COX2. It is possible that resolvins down-regulate produc-
tion/activity of COX2 and other inflammatory mediators
through a process that involves microRNAs (miRs) because
recent findings by Rechiuti and colleagues (71) indicate that
RvD1 can accelerate resolution of an inflammatory process
by fine-tuning regulatory miRs. These authors showed that
in a mouse model of acute peritonitis, RvD1 treatment signif-
icantly changed the levels of several miRs whose putative tar-
gets (also relevant to ENDO) include but are not limited to
interleukin-6 and transforming growth factor, beta receptor
1 (increased miR-142-3p); cAMP response element-binding
protein (increased miR-142-5p); signal transducer and acti-
vator of transcription 5 (decreased miR-203); and TNF-a,
TNF-a receptor, interleukin-1, and its accessory protein
(increased miR-219) (71).
In conclusion, clinical trials with resolvin-based products
from Resolvyx Pharmaceuticals, Inc. are underway (www.re
solvyx.com/products/index.asp). These investigations
include patients with different inflammatory diseases (dry
eye, rheumatoid arthritis, irritable bowel syndrome, cardio-
vascular disease) but not women with ENDO. These trials
are in different phases of research, but to our knowledge no
published reports are yet available. In conclusion, RvD1 and
17(R)-RvD1 can alleviate inflammatory signs such as
increased vascular permeability and abnormal sensitivity
from the pelvic area associated with ENDO. Given their effec-
tiveness in reducing multiple inflammatory signs and lack of
known aversive effects, the results here, together with the
considerations above, suggest that RvD1 and 17(R)-RvD1
can be considered for further investigation of their therapeu-
tic potential for treating ENDO.
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