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Keywords: PCOS, obesity, inflammation, specialized pro-resolving
mediators (SPMs)
Key Clinical Message : SPMs, which derive from 18-HEPE, 17-HDHA and
14-HDHA, and are biosynthesized from their respective precursor
omega-3-fatty acids EPA and DHA, have a possible influenece on the
resolution of inflammation associated with polycystic ovary snydrome.
Abstract:
PCOS represents a chronic disease affecting between 8 -10 % of women
during their reproductive life. Concepts were developed that re-define
inflammation as being composed of the inflammatory response and active
resolution processes, which occur at the same time. Key players are the
specialized pro-resolving lipid mediators (SPMs).
Introduction
The Polycystic Ovary Syndrome (PCOS) is a disease that causes irregular
bleeding, chronic anovulation, androgen excess, and a typical ovarian
ultrasound feature [1]. It affects
between 5 and 10 % of women in their reproductive age, thus
representing one of the most frequent causes of infertility [2]. The
reasons for the development of a PCOS have not been resolved yet.
Genetic predisposition, together with the gestational environment and
lifestyle factors seem to be key contributors. The European Society of
Human Reproduction and Embryology and the American Society for
Reproductive Medicine defined the criteria for the definition of this
disease [3,
4] at a meeting in Rotterdam in 2003.
Apart from the symptoms mentioned above, 30-40% of women with PCOS show
a reduced glucose tolerance [5], often accompanied by insulin
resistance, which both are independent of body mass index (BMI). 80% of
the obese women and 30-40% of the lean individuals with PCOS suffer
from hyperinsulinemia [6,7]. Hence, these aspects have been
addressed by several studies to reach a general agreement on diagnostic
criteria. It has been found that hyperinsulinemia is a key factor in the
clinical pathogenesis of PCOS with its characteristic symptoms such as
hyperandrogenism, chronic anovulation, typical PCOS ultrasound images,
and skin issues such as acne, hirsutism, and seborrhea and seems to be
independent of weight [8]. Excess insulin may lead to enhanced
androgen synthesis by direct stimulation of the androgen production on
the one hand and by reducing the serum levels of sex hormone-binding
globulin (SHBG) on the other side [9].
However, the manifestation of PCOS is heterogeneous, and its
etiopathology is still unclear [10,11]. As proven by familial
clustering of PCOS incidence, results from twin studies, and the fact
that specific endocrine and metabolic features of PCOS are heritable,
genetic factors play an important role in the pathogenesis [10, 11,
12]. It was further shown that embryos, which are exposed to unusually
high levels of androgens and anti-Müller-hormone (AMH), have an
increased risk for developing a PCOS later in life [13]. Additional
factors, such as obesity, further have a substantial impact on the
severity of PCO symptoms [14, 15].
Obesity and inflammation
A state of chronic systemic inflammation is characteristic of obesity
and can be determined by measuring increased serum levels of
inflammatory cytokines and altered frequencies and functions of
peripheral blood lymphocytes [16, 17, 18]. These changes are
manifested at the tissue level and in adipose-, liver- and other tissue
beds [17, 18]. They might be responsible for comorbidities that are
often related to obesity, such as atherosclerosis, diabetes, and
steatohepatitis [19, 20, 21, 22, 23]. This kind of inflammation is
often attributed to irregularities in innate immunity. However, innate
and adaptive immune systems are closely interlinked, and consequently,
obesity-related inflammation is associated with both processes [24].
Inflammatory processes occur due to traumatic events or infections and
are also crucial for the turnover of cells during aging [25]. In
this context, it is involved in the regulation of essential processes
associated with cellular homeostasis, such as proliferation, necrosis,
and apoptosis. Consequently, also by-products of cell necrosis and
apoptosis, i.e., endogenous stimuli, can trigger inflammatory responses
that are necessary for the regulation of tissue turnover. In obese
individuals, systemic levels of free fatty acids are elevated, for
example. These molecules are primary ligands of Toll-like receptors,
which themselves are critical regulators of the innate immune response
[26, 27]. In this way, the systems, which regulate obesity and
inflammation, are linked directly.
From a molecular point of view, there is significant crosstalk between
the intracellular signalling pathways of inflammation and glucose
homeostasis, since they have multiple signalling mediators in common.
A further relationship between inflammation and the metabolic system is
visible on the cellular level, since adipocytes and macrophages are
closely related, and their evolution might be traced back to a
conventional primordial precursor cell [28].
It has also been demonstrated that insulin resistance and inflammatory
processes are closely linked and may stimulate each other [29].
Both, subclinical inflammation and insulin resistance are essential
makers for the development of cardiovascular disease [30] and for
women with PCOS, whose cardiovascular risks are elevated, a connection
between inflammation and their hormonal-metabolic features were also
shown [31].
If obesity and inflammation are correlated, it is worthy of looking at
the possible pathways of inflammation that accompany or influence the
obesity in PCOS women considering the modern perception of inflammatory
processes.
The role of inflammation
In many chronic diseases, including vascular and neurological disorders,
as well as metabolic syndrome, excessive inflammatory processes are
manifested, thus representing a public health concern. If the endogenous
control points within the inflammatory pathways were understood
completely, the pathogenesis of the diseases might become more explicit,
and new approaches for treatment might be found.
When a host experiences a trauma, barrier breakage, or microbial
invasion, potential invaders must be eliminated, the location must be
cleared, and affected tissue must be remodelled and regenerated. For the
acute inflammatory response, several lipid mediators are crucial. They
include eicosanoids (prostaglandins and leukotrienes), which derive from
arachidonic acid, an essential fatty acid [32, 33], and different
cytokines and chemokines [35, 35, 36]. These molecules interact with
each other, thereby further intensifying the inflammatory process that
may, in turn, be counteracted with pharmacological inhibitors and
receptor antagonists. Since inflammatory processes are involved in many
prevalent diseases, it is necessary to broaden the knowledge of all
mechanisms involved in order to improve the therapeutic options.
Historically, the inflammatory response used to be separated into an
active initiation and a passive resolution process [37]. Recently,
however, mediators were identified which have pro-resolving capacities
and can be synthesized from omega-3 (n-3) essential fatty acids (EFA).
Studies have shown that the resolution process can be ”switched on” in
animal models and may thus rather be an active response in the
self-limitation of acute inflammation than a passive dilution of
chemo-attractants [38, 39].
Molecules, which are supposed to act as mediators, must be supplied in
enough amounts in order to lead to reactions in vivo. For EPA and DHA,
anti-inflammatory properties have been proposed for many years. These
omega-3 fatty acids compete with arachidonic acid in reducing
pro-inflammatory eicosanoids [40]. However, the underlying molecular
mechanisms had remained obscure until recent results emerged, and
whether EPA or DHA is more relevant for human health or therapeutic
options is still under debate [40].
It has been shown for resolving inflammatory exudates that omega-3 fatty
acids serve as substrates for the synthesis of specific signalling
molecules – the so-called specialized pro-resolving mediators (SPMs),
which comprise resolvins, protectins, lipoxins and maresins (Fig. 1).
These findings triggered new studies concerning the resolution pathways
and the immune mechanisms underlying homeostasis. It was shown in animal
models that SPMs promote critical paths of the inflammatory resolution,
as they limit the infiltration of polymorphonuclear neutrophils and the
elimination of apoptotic cells by macrophages [41]. (see figure 1).
Active resolution of inflammation
Inflammations may be resolved entirely or become a chronic state.
Formerly, resolution of active inflammation has been considered a
passive event, upon which inflammatory mediators such as prostaglandins
or cytokines were merely diluted, thus disappearing from the site of
inflammation. This would finally lead to prevent leukocyte infiltration
into the tissue. However, Serhan et al. provided new evidence to revise
this theory by demonstrating the existence of an active resolution
process mediated by so-called selective pro-resolving mediators (SPMs)
in several studies. The SPM molecular superfamily contains subgroups
named resolvins (Rvs), protectins, maresins, and lipoxins. The
biosynthesis of the SPMs (with lipoxygenases and cyclooxygenases
intervening both on the pathways of eicosanoids and SPMs), as well as
the corresponding cell membrane receptors, have been described. SPMs are
crucial for sufficient resolution of inflammatory processes, and based
on these new findings, Serhan et al. described three novel pathways for
the potential development of acute inflammation. They include the action
of the SPMs, as well as crucial endogenous control mechanisms and, are
illustrated in Fig. 2.
Importantly, within this new perception of inflammatory processes, the
resolution is an active mechanism, which does not start with a delay,
but at experimental timepoint Zero.
Alfa signals Omega throughout the course of inflammation, mainly SPMs
were found to repress inflammatory signals by ending tissue infiltration
of neutrophils and preventing further recruitment of immune cells to the
site of inflammation. Subsequently, phagocytic macrophages are
stimulated, which further leads to increased clearance and elimination
of apoptotic polymorphonuclear neutrophils (PMNs) by efferocytosis and
phagocytosis [35].
SPMs are synthesized from eicosapentaenoic acid (EPA, C20:5n-3) and
docosahexaenoic acid (DHA, C22:6-3). Both are omega-three
polyunsaturated fatty acids (PUFAs) and serve as precursors in the
biochemical pathways leading to SPMs via the metabolites 18-HEPE,
17-HDHA, or 14-HDHA (see Fig. 3) [44].
Since the development of this new concept of inflammation, many tissues
have been suitable targets for treating inflammation with SPMs or their
active precursors 18-HEPE, 17-HDHA and the 14-HDHA, in order to elicit
dynamic resolution of inflammation. In contrast to traditionally applied
anti-inflammatory therapies, they are do not act as immunosuppressors,
and debris is cleared, thus being potentially useful for the treatment
of chronic inflammation. Substances, which are applied nowadays, have
distinct disadvantages: steroids may interfere with wound healing, can
promote osteoporosis, and is immunosuppressive. NSAIDs may lead to
stomach bleeding, are potentially toxic for the cardiovascular system
and the kidneys and interfere with wound healing. Cyclooxygenase (COX)2
inhibitors constitute a risk factor for cardiovascular and
thromboembolic events. Anti-TNF therapies for blocking cytokines lead to
increased rates of infections and enhance the risk of lymphoma
development.
SPMS, on the other hand, was shown to increase the killing of microbial
invaders and their clearance by immunocytes. It was demonstrated that
they down-regulate infiltration and recruitment of PMN, enhance
phagocytosis, and efferocytosis (M1 to M2). Application of SPMs also
decreased the level of pro-inflammatory chemical mediators, while
increasing the number of anti-inflammatory mediators like IL-10, for
example. Finally, they can reduce inflammatory pain, stimulate the
regeneration of inflamed tissue, and promote wound healing (see figure
4).
Obesity and inflammation
In obesity, adipose tissue is characterized by high levels of
pro-inflammatory eicosanoids and depleted levels of SPMs. DHA EPA is
required, but enzymes are critical to the formation of the SPMs circuit.
SPMs increase M2 polarization of adipose tissue macrophages. In some
inflammatory conditions, lack of SPMs has been related to the inability
of immune cells for processing SPM substrate (EPA /DHA); thus,
supplementation with EPA and DHA would be ineffective in restoring SPMs
level. In those cases, supplementation with 17HDHA and 18HEPE (advanced
SPMs intermediates also derived from DHA and EPA) could be effective in
restoring SPMs levels [45] (see figure 5).
Administration of 17HDHA and other SPMs could be more efficient in
overriding impaired formation of SPMs in conditions characterized by
dysfunctional LOX activity. This disfunction are known and described in
figure 6.
Conclusions:
Taking into consideration that PCOS has no cure [46] and
that treatment should involve lifestyle changes such as weight loss and
exercise [47,48] the
birth control
pills may help with improving the regularity of periods, excess hair
growth, and acne.
Metformin and anti-androgens may
also help. Other typical acne treatments and hair removal techniques may
be used [46].
Inositols have also been used for the improvement of the disease, and
efforts to improve fertility include weight
loss, clomiphene, or
metformin and
In vitro
fertilization.
All these preventive actions are on the other site, only symptomatic
treatments.
Pro-resolving mediators derived from of omega-3 fatty acids
The anti-inflammatory process is not synonymous with the pro-resolution
process, in which SPMs as agonists stop the immigration of neutrophils
and activate non-phlogistic macrophage reactions and resolution
programs.
This difference became clear when new families of anotacoids and their
descendants were identified, which can be activated by aspirin. This
provided evidence in animal models that the resolution process is
actively controlled by lipid mediators. Investigating and using this
mechanism is an important challenge for the future as omega-3 fatty
acids are currently widely used as dietary supplements but are
prescribed by medical providers in less than 25% of cases. This is due
to the fact, that their therapeutic benefits are assessed differently in
clinical trials. This reinforces the importance to understand the
mechanisms underlying their effect.
It was only by using a model system with resolving mouse exudates that
the metabolic pathways and effects of the SPMs could be identified.
Since then, each resolvin ((RvE1, RvD1, RvD2, RvD3 and RvD5),
protectines and maresine synthesized by leukocytes could be compared
with completely organo-chemically synthesized molecules and described
stereochemically [41, 49].
Models of chronic inflammatory diseases
Periodontitis is a chronic inflammatory disease in which infection leads
to a tissue injury around the tooth that is neutrophil-mediated.
Activated neutrophils produce PGE2, LTB4 and LXA4 in patients with
periodontitis. PGE2 leads to bone loss in this tissue. P. gingivalis
causes the recruitment of neutrophils in Air Pouch mouse models as well
as a high regulation of COX-2. Stable LXA4 analogues reduced both
neutrophil inflow and COX-2 expression associated with the oral
pathogen. In addition, P. gingivalis increased the expression of COX-2
in the lungs and heart of mice. Also, ribosomale 16S RNA of P.
gingivalis was present in these tissues, which provided evidence of a
role of this oral pathogen in the development of systemic inflammation.
Transgenic rabbits that overexpress human lipoxygenase type I produce 6
to 10 times as much LXA4 as wild rabbits [50]. These transgenic
rabbits show lower bone loss in periodontitis, significantly reduced
recruitment of neutrophils, and vascular permeability of the skin when
compared to wild rabbits when stimulating the immune system. This
suggests that overexpression of lipoxin biosynthesis has a protective
effect and this finding could be useful in controlling
inflammation-dependent bone degradation.
Unexpectedly, the overexpression of 15-lipoxygenase in these transgenic
rabbits drastically reduces the onset of atherosclerotic lesions. In
transgenic 12/15 lipoxygenase mice, RvD1, PD1 and 17-HDHA with reduced
PGE2 were identified in activated macrophages (LC-MS-MS analysis
[51]. LXA4, PD1 and RvD1 reduced the number of cytokines from
endothelial cells (e.g. MCP-1) and adhesion molecules (P-Selectin and
VCAM-1), but not ICAM-1. LXA4, PD1 and RvD1 also improved the uptake of
apoptotic thymocytes, which could contribute to the antiatherogenic role
of this pathway in mice. This process can also be influenced by diet to
influence the severity of atherogenic lesions [51, 52]. RvE1 is
protective of periodontitis. In contrast to LXA4, however, exogenous
RvE1 also stimulates bone regeneration in the rabbit model for
periodontitis [53]. In the murine arthritis model, RvD1 and 17-HDHA
reduce pain and tissue damage, shown to be stronger than steroid or pain
treatments [54].
Unresolved inflammation, epithelial and microvascular injuries can lead
to excessive fibrosis, which impairs organ function. Leukotrienes are
professionally effective; and in people with sclerodermal interstitial
lung disease, LXA4 is found in the lungs in quantities that do not
appear to be enough to counteract the pro-fibrotic factors [55]. In
animals, an exogenous aspirin-triggered lipoxin analogue reduces
pulmonal fibrosis (triggered by the antibiotic bleomycin [56]) and
both LXA4 and benzo-LXA4 reduce fibrosis in kidneys [57, 58]. The
exogenous administration of RvE1 and RvD1 protects against renal
fibrosis by reducing collagen I and IV, A-SMA and fibronectin. In
addition, exogenously administered RvD1 reduces the occurrence of
pro-inflammatory mediators formed in response to cigarette smoke and
lung toxins [59].
If uncontrolled, chronic inflammation may result in numerous diseases,
including obesity and diabetes [60]. In both diseases, peripheral
blood markers of inflammation are present in elevated levels after
intake of a pro-inflammatory western type diet [61]. Based on these
data Hansen et al. postulated that the use of protectins will be a major
step forward in the management of obesity [62]. In a recent study it
could be shown that resolvin D1 activates lipoxin A4/formyl peptide
receptor 2 (ALX/FPR2), which facilitates cardiac healing. The lack of
ALX/FPR2 led to the development of spontaneous obesity and diastolic
dysfunction with reduced survival with aging and it amplified leukocyte
dysfunction and facilitated profound interorgan non resolving
inflammation [63].
All these examples show the ability of SPMs and their precursors to in
fluence positively the pro-resolving axis of chronic diseases like the
PCOS.
The use of naturally occurring bioactive lipid mediators derived from
DHA and EPA, therefore, promises new tools to try to reduce the circulus
vicious of visceral adiposities in PCOs women and the corresponding
inflammation.
Hence the use of 18-HEPA, 17-HDHA, and 14-HDHA maybe a new approach in
this disease.
Funding:
Not applicable. No funding.
Conflict of Interest:
Pedro-Antonio Regidor is employee of Exeltis Healthcare, Anna Müller and
Manuela Sailer are emploeyees of Exeltis Germany, Fernando Gonzalez
Santos is employee of Solutex Spain, Jose Miguel Rizo is employee of
Chemo Spain, Fernando Moreno Egea is CEO of Solutex Spain
Ethical approval: This article does not contain any studies with human
participants or animals performed by any of the authors.
Author Contribution
Pedro-Antonio Regidor
Responsible for the concept of resolution of inflammation in PCOS
Anna Müller
Responsible for lietrature research
Manuela Sailer
Responsible for graphic design
Fernando Gonzalez Santos
Responsible for the development of SPMs use in humans and therfeore for
basic scientific data
Jose Miguel Rizo
Responsible for PCOS chapter and data aquisition
Fernando Moreno Egea
Responsible for coordination of the manuscript
Acknowledgment:
Tobias Hummel from die kommunikatöre for the design of the figures
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Legends:
Figure 1: The current model of inflammatory processes (modified from
Serhan and Levy [42]).
Figure 2: Novel description of the potential development of inflammatory
responses (modified from Serhan [43]).
Figure 3: PEA and DHA metabolic pathways (modified from Serhan
[44]).
Figure 4: The pathway of efficacy of the mediators (modified from Serhan
[43]).
Figure 5: The use of 17-HDHA and 18-HEPE enhanced the amount of SMP´s in
fat cells in comparison to cells of healthy weight probands (modified
from Lopez Vicario [45]).
Figure 6: Pathway from DHA to the D resolvins (modified from Lopez
Vicario [45]).