The role of pro-resolution lipid mediators in infectious disease
Short title: pro-resolution lipid mediators in infection
Clark Donald Russell1 and Jürgen Schwarze1*
1 University of Edinburgh, Queen's Medical Research Institute, MRC Centre for
*Corresponding author: Professor Jürgen Schwarze. University of Edinburgh, Queen's
Medical Research Institute, MRC Centre for Inflammation Research, 47 Little France
Crescent, Edinburgh, Midlothian, UK EH16 4TJ. Tel: 0131 2426588. Email:
ARDS (acute respiratory distress syndrome); PUFA (polyunsaturated fatty acid); AA
(arachadonic acid); DHA (docosahexaenoic acid); SOCS2 (suppressor of cytokine
signalling 2); IL (interleukin); IFN (interferon); TNF (tumour necrosis factor); RSV
(respiratory syncytial virus); HIV (human immunodeficiency virus); BPI
(bactericidal/permeability-increasing protein); ROS (reactive oxygen species); ALI
(acute lung injury); BAL (broncoalveolar lavage); MPO (myeloperoxidase).
Inflammation is an essential host defence against infection, but can be damaging when
excessive. Resolution of inflammation is an active process, and the pro-resolution
effects of lipoxins, resolvins and protectins have received significant interest. Here, we
review emerging data on the role of these lipid mediators in infectious disease.
Lipoxins influence host control of Mycobacterium tuberculosis, Toxoplasma gondii,
Trypanosoma cruzi and Plasmodium bergehei cerebral malaria in mice. Their effects are
protective in toxoplasmosis, T. cruzi infection and cerebral malaria but detrimental in
tuberculosis; related to the balance between pathogen-control and excessive immune
response. Topical lipoxin abrogates the tissue damage seen in a rabbit model of
Porphyromonas gingivalis periodontitis. The increased virulence of H5N1 influenza A
virus in mice correlates with reduced expression of SOCS2, required to mediate the
effects of lipoxin. Mice unable to synthesise lipoxin suffer increased lung pathology
during respiratory syncytial virus infection. Protectin suppresses Influenza A virus
replication in vitro and increases survival in a mouse model of severe influenza
Resolvins were investigated in a number of animal models of systemic bacterial
infection, and were found to enhance phagocytic clearance of bacteria, reduce
inflammation severity, promote neutrophil apoptosis, modulate neutrophil chemotaxis
and importantly reduce mortality. Interestingly, resolvin also enhances the antibacterial
effect of ciprofloxacin and vancomycin. Topical resolvin application reduces the
severity of herpes simplex virus ocular infection in mice.
If the effects of these mediators translate from pre-clinical studies into successful
clinical trials, they represent promising new strategies in managing infectious disease.
Inflammation is an essential host defence mechanism, required for protection against
pathogenic micro-organisms and viruses. However, an excessive and non-resolving
inflammatory response is damaging to the host. For example, in sepsis there is loss of
homeostatic control over the inflammatory response mounted against an infectious
agent, resulting in a pro-inflammatory, pro-coagulant state that can result in organ
dysfunction and death. Acute respiratory distress syndrome (ARDS) is another example,
and describes the life-threatening hypoxic complication of excessive pulmonary
inflammation that can be triggered by a range of insults, including pneumonia and
sepsis . Chronic, non-resolving inflammation also underpins a number of other
pulmonary diseases, including asthma, cystic fibrosis and bronchiectasis. Inflammatory
bowel disease and rheumatoid arthritis are extra-pulmonary examples of this.
Resolution of inflammation and restoration of normal tissue function are therefore
critical events following the clearance of an infectious agent, in order to prevent the
development of these ‘complications’ of excessive inflammation. This is now known to
be an active process, termed catabasis , driven by the pro-resolution lipid mediators
resolvin, protectin and lipoxin . Lipoxins (trihydroxy-tetraene-containing
eicosanoids) are derived from the omega-6 polyunsaturated fatty acid (PUFA)
arachadonic acid (AA) through sequential reactions involving lipoxygenase enzymes
(including 15-lipoxygenase type 1 and 5-lipoxygenase in human mucosal tissues) [4, 5].
Resolvins are derived from omega-3 PUFAs and exist as two series (D and E). D-series
resolvins are products of docosahexaenoic acid (DHA) metabolism involving 15-
lipoxygenase. E-series resolvins are synthesised from eicosapentaenoic acid involving
aspirin-acetylated cyclo-oxygenase 2 . Protectins are also omega-3 PUFA derivatives,
generated from DHA through a 15-lipoxygenase-mediated pathway . The pro-
resolution effects of these mediators are exemplified by their role in pulmonary
inflammation, the setting in which they are best studied. Resolvins, protectins and
lipoxins all have a pro-resolution role in a mouse model of allergic airway inflammation
[8, 9, 10, 11].
Given that an excessive inflammatory response is implicated in the pathogenesis of a
number of infectious diseases and their complications, including sepsis syndrome and
ARDS, we conducted a review of the literature to determine what is currently known
about the role of the pro-resolution lipid mediators lipoxin, resolvin and protectin in
Influenza A virus. Cilloniz et al used a mouse model to investigate Influenza A virus
virulence, comparing host transcriptional responses to infection with reconstructed 1918
H1N1 virus to avian H5N1 virus (Vietnam/1203) . This highly pathogenic avian
H5N1 virus is more virulent in humans than the 1918 H1N1 virus, with a case-mortality
rate of 60% compared to 2.5% . In mice, H5N1 was more virulent (infection
resulted in shorter survival time) than the H1N1 strain and disseminated to extra-
pulmonary sites (brain and spleen) following intra-nasal inoculation. Global
transcriptional responses to infection were analyzed and showed that the different
strains of Influenza A virus caused different early responses in gene expression, and that
many of the differentially regulated genes were components of the inflammatory
response. H5N1 infection was associated with up-regulation of inflammasome genes
(including caspase 1 and IL-1), tumour necrosis factor-α, IFN-γ and protein kinase R, as
well as other inflammation related genes. Using a bioinformatics approach to analyse
gene expression, the authors found that extra-pulmonary dissemination was associated
with down-regulation of genes involved in mediating the pro-resolution effects of
lipoxin on leukocyte recruitment and counter-regulation of pro-inflammatory cytokine
induction. These included the suppressor of cytokine signalling (SOCS) 2 gene, the
product of which is activated by lipoxins and is an essential intracellular mediator of
lipoxin’s effects on inflammatory cell trafficking and cytokine induction . Therefore,
loss of lipoxin’s pro-resolution effects may be associated with greater Influenza A virus
virulence, suggesting a protective role for lipoxin in this infection, possibly related to
the suppression of pro-inflammatory cytokines that are up-regulated in this model. The
highly pathogenic avian H5N1 virus used in this study was less successful at spreading
between human hosts compared with other Influenza A virus strains, for example the
2009 H1N1 pandemic strain. A successful pathogen minimises damage to its host to
prolong the availability of its replicative niche and the high case-mortality seen with
infection by this H5N1 strain indicates that it is not well adapted to humans. Reduction
of lipoxin-mediated pro-resolution effects may contribute to the virus’ poor adaptation
Respiratory syncytial virus. In a recent study, respiratory syncytial virus (RSV)
infection of mice deficient in 5-lipoxygenase, an enzyme required for lipoxin production,
failed to elicit alternative macrophage differentiation, which is known to be required for
the resolution of RSV-induced lung injury [15,16]. Alternatively activated macrophages
are thought to induce anti-inflammatory cytokine expression and drive lung tissue repair
. Significantly, RSV infection of these 5-lipoxygenase deficient mice resulted in
greater lung pathology on histological analysis (increased peribronchiolitis,
perivasculitis, interstitial pneumonitis and alveolitis) in comparison to infected wild
type mice . Treatment with lipoxin A4 and resolvin E1 partially restored the
alternatively activated macrophage phenotype in the 5-lipoxygenase deficient mice.
These observations support a pro-resolution role for lipoxins in viral respiratory tract
Other respiratory viruses. Alveolar macrophages are the major resident inflammatory
cell of the respiratory tract and are able to produce lipoxins. Alveolar macrophages
isolated from rats that had previously been infected with a range of respiratory viruses
(murine parainfluenza virus type 1, rat coronavirus, pneumonia virus of mice and mouse
adenovirus) produced higher levels of lipoxin than macrophages from rats that had been
kept sterile since birth . These findings suggest that virus-induced pulmonary
inflammation is a stimulus for the production of lipoxins.
Human immunodeficiency virus (HIV). In a cell culture model of HIV central
nervous system infection, following co-culture of HIV infected monocytes with
astroglia, TNF-α and IL-1β were produced and this production correlated with synthesis
of large amounts of leukotriene B4, leukotriene D4 and lipoxin A4 . This is the only
study to demonstrate, albeit in vitro, that lipoxins are produced in direct response to
viral infection. However, the role of lipoxin in this model of infection has not been
Mycobacterium tuberculosis. Following aerosol infection with M. tuberculosis, mice
have been shown to produce high levels of lipoxin A4 during chronic infection .
Pulmonary endothelial cells and macrophages were responsible for this. Transgenic
mice deficient in 5-lipoxygenase, an enzyme required for lipoxin production, were able
to control M. tuberculosis infection better than wild type mice, as demonstrated by
lower pulmonary and splenic titres of viable M. tuberculosis (at 21 and 42 days) . On
histological examination of lung tissue, extensive inflammation and areas of necrosis
were seen in wild type mice whereas the transgenic mice had a lesser degree of
inflammation and little evidence of necrosis. Importantly, the transgenic mice unable to
produce lipoxin enjoyed enhanced survival in this model of M. tuberculosis infection
and had increased pulmonary levels of IL-12, IFN-γ and inducible nitric oxide synthase
(NOS2) which is known to have a protective role in host control of M. tuberculosis
infection in mice . Oral administration of a lipoxin A4 analogue reversed the
enhanced control of infection in the transgenic mice, and splenocytes from these mice
showed reduced IFN-γ production.
Toxoplasma gondii. In a mouse model of T. gondii infection (established via
intraperitoneal inoculation of T. gondii cysts), serum levels of lipoxin A4 rise during
infection and remain high once chronic infection has been established . Transgenic
mice unable to produce lipoxin A4 suffered increased mortality following infection,
compared to wild type control animals [21, 14]. Interestingly, fewer T. gondii brain
cysts were seen in the lipoxin deficient mice and consistent with this, lower parasitic
burden and increased serum levels of IL-12 and IFN-γ were seen when compared to
wild type mice. Therefore, it seems likely that the increased mortality of the lipoxin
deficient mice is attributable to cytokine-mediated tissue damage, despite better parasite
control. Corroborating this, increased histological severity of meningitis and
encephalitis was observed in the transgenic mice. Administration of a lipoxin analogue
rescued the lipoxin deficient mice from this fatal phenotype and lowered IL-12 and
IFN-γ levels (to wild type levels in the case of IFN-γ).
IL-12, produced by antigen presenting cells such as dendritic cells, has an important
role in host control of intracellular pathogens such as T. gondii and viruses, but in
excess can cause immuno-pathology. In mice, it has been shown that lipoxin A4
analogues suppress IL-12 production by dendritic cells stimulated with T. gondii extract
. Whilst this may be a host-driven response to curb excessive inflammation,
induction of lipoxin production could be a strategy adopted by pathogens to modulate
host immunity and perhaps facilitate chronic infection by reducing tissue damage.
The contrasting roles of lipoxins in these two models of infection may relate to the
dynamics of the specific pathogen-host interactions. T. gondii replicates quicker than M.
tuberculosis and the risk of excessive inflammation and ensuing immuno-pathology
may therefore be greater . By preventing this, lipoxins are beneficial to the host,
hence enhance survival. M. tuberculosis induces a weaker TH1 response in mice than T.
gondii and replicates more slowly, therefore the enhanced inflammatory response seen
in the lipoxin deficient mice may be advantageous, by ‘topping-up’ existing host control.
The reduced tissue damage seen in lipoxin deficient mice may be due to better control
of M. tuberculosis replication. It is also important to note that the local (lung versus
peritoneum/brain) biosynthesis and actions of lipoxin may differ between these two
infection models and could provide an alternative explanation for the different outcomes
Trypanosoma cruzi (Chagas’ disease). In a mouse model of Trypanosoma cruzi
infection, it was found that the administration of aspirin (acetylsalicylic acid) at doses of
25 or 50mg/kg increased survival and decreased peak parasitaemia, whereas higher or
lower doses had no effect . The aspirin-triggered lipoxin, 15-epi-lipoxin A4, was
found to be increased by administration of aspirin in both in vitro and in vivo models of
infection, with infection alone also increasing 15-epi-lipoxin A4 levels. Exogenous
administration of 15-epi-lipoxin A4 was found to decrease parasitaemia peaks and
decrease cardiac inflammation and increase survival. The authors therefore
hypothesised that the beneficial effect of aspirin on infected mice was due to production
of 15-epi-lipoxin A4. This may represent a new therapeutic strategy in the acute phase
of Chagas’ disease.
Cerebral malaria. Wild type and 5-lipoxygenase-deficient mice were infected with
Plasmodium berghei-ANKA in a model of cerebral malaria . Wild type mice
enjoyed significantly increased survival in comparison to 5-lipoxygenase deficient mice.
Levels of parasitaemia were similar between groups, but lipoxin deficient mice had an
increased cerebral parasite burden after 5 days despite reduced cerebral inflammation
and less CD8+IFN-γ+ T-cells in brain tissue. The lipoxin deficient mice were found to
have higher serum levels of IL-12 and IFN-γ, both of which are associated with the
pathogenesis of murine cerebral malaria. Significantly, treatment with 15-epi-lipoxin
A4 significantly prolonged survival in both wild type and lipoxin deficient mice, as well
as reducing expression of IL-12 and IFN-γ in the brain. The mortality rate did not differ
significantly if lipoxin was administered on the day of infection or three days later.
Lipoxin therefore appears to increase host survival in a mouse model of cerebral malaria
by limiting inflammation, not enhancing control of parasite levels.
Periodontitis. Serhan and co-workers used a rabbit model of periodontitis to investigate
the effects of lipoxin in this infection . The application of a dental ligature plus
Porphyromonas gingivalis resulted in soft tissue loss, histological (leukocyte infiltrates)
and radiological (bone loss) features of periodontitis in wild type rabbits. The authors
then used a transgenic rabbit that over-expresses the enzyme 15-lipoxygenase, resulting
in 3-4x increased lipoxin production. In these transgenic animals, following the same
procedure to establish periodontitis, none of the clinical, histological or radiographic
features were found. In the wild type animals, bone loss could be prevented by the
administration of intravenous metronidazole, confirming that P. gingivalis infection was
responsible for the features seen. Wild type rabbits subject to periodontitis induction
were then administered a topical lipoxin analogue and this protected the animals from
gross soft tissue destruction, leukocyte accumulation and bone loss. Periodontitis is an
infectious disease, though the tissue damage characteristic of the condition is thought to
be driven by an aberrant host response to infection . In this set of experiments,
Serhan et al demonstrate that lipoxin has a role in curbing this excessive response and
that this has a protective effect in vivo.
Salmonella typhimurium. By performing transcriptional profiling of model epithelial
cells exposed to lipoxin, Canny et al found that lipoxin up-regulated the expression of
bactericidal/permeability-increasing protein (BPI) . BPI is an innate immune
defence molecule that is active against Gram negative bacteria, via bactericidal effects
on bacterial cell membranes, neutralisation of lipopolysaccharide and as an opsonin.
This was then confirmed in four other epithelial cell lines (OKF6, T84, Caco2 and
pulmonary epithelial cells A549). Building on the known bactericidal effect of
epithelium-derived BPI on Gram negative bacteria, the authors sought to examine the
effect of lipoxin on epithelial killing of Salmonella typhimurium. Epithelial cell culture
was pre-exposed to lipoxin analogue and then incubated with S. typhimurium. This
resulted in concentration-dependent increased bacterial killing compared to non-pre-
treated cultures. This enhanced bactericidal activity could be significantly inhibited by
the addition of anti-BPI, indicating that induction of BPI was largely responsible for this
lipoxin-mediated enhanced killing of S. typhimurium. Interestingly, in a mouse model of
(non-infectious) dextran sodium-sulfate induced colitis, oral administration of lipoxin
analogue reduced weight loss, passage of blood per rectum and mortality, affirming its
role in gastrointestinal mucosal inflammatory conditions .
Sepsis. Caecal ligation and puncture in mice establishes microbial sepsis that is
considered similar to the pathophysiology of sepsis in humans . In this model, in
comparison to a control treatment, intravenous administration of resolvin D2 reduced
the viable bacterial load in blood and peritoneal exudates (in the absence of direct
antibacterial effects) and reduced neutrophil migration into the peritoneal cavity. In
addition, histological evidence was seen of enhanced phagocytosis of bacteria in
inguinal lymph nodes and in vitro, incubation with resolvin D2 enhanced zymosan
phagocytosis by macrophages obtained from the peritoneum of resolvin naïve mice.
When incubated with resolvin D2, human neutrophils demonstrated enhanced
phagocytosis of Escherichia coli and also increased intracellular production of reactive
oxygen species (ROS). Furthermore, plasma levels of pro-inflammatory cytokines (IL-6,
IL-1β, IL-23 and TNF-α) were reduced in resolvin D2 treated mice. Importantly, the
effect of these pro-resolution actions of resolvin was to increase survival from sepsis in
this mouse model.
Chiang et al investigated the effects of resolvin using a mouse model of E. coli
peritonitis, involving intraperitoneal inoculation of E. coli . They found that the
intra-peritoneal administration of resolvin D5 enhanced phagocytosis of bacteria in
comparison to mice inoculated with E. coli without resolvin. Resolvin D1 had a similar
but lesser effect. Administration of resolvin (D1 or D5) was also associated with a
significantly lower titre of viable bacteria in the blood and peritoneal exudate, as well as
a lesser degree of hypothermia. Importantly, resolvin D1 increased survival in this
model. As for the model of microbial sepsis discussed previously, plasma levels of pro-
inflammatory cytokines (including TNF-α and IL-1β) were reduced by resolvin
administration. Interestingly, it was found that resolvin D1 enhanced the antimicrobial
effect of ciprofloxacin in resolving E. coli peritonitis. When given in combination,
resolvin and ciprofloxacin had an additive effect on reducing the ‘resolution interval’
(time from maximum concentration of peritoneal leukocytes to 50%), greater than either
agent given alone. In addition, the combined administration of ciprofloxacin and
resolvin D1 resulted in lower titres of viable bacteria in blood and peritoneal exudate,
and enhanced macrophage phagocytic activity (not seen with either agent alone). The
effect of reducing bacterial titres was still seen even when ciprofloxacin was
administered at sub-optimal concentrations with a cocktail of resolvin D1, D5 and
protectin D1. In Staphylococcus aureus skin infection, using mouse dorsal skin pouches,
resolvins D1 and D5 plus protectin D1, when administered with vancomycin (at a sub-
optimal concentration) into the pouch, enhanced the clearance of bacteria, resulting in
lower viable bacterial titres in pouch exudate and reduced neutrophil infiltration. This
effect was also seen when either resolvin or vancomycin were administered alone, but
again, an enhanced effect was seen when both were given together.
Burns-related sepsis. Infection secondary to burns is an important clinical problem and
burns-related sepsis is responsible for significant mortality in burns patients. Using a rat
model of burn injury, Kurihara et al demonstrated that neutrophils isolated from burned
rats were impaired in their ability to migrate towards a chemoattractant . This defect
in neutrophil chemotaxis could result in an inability of neutrophils in burns patients to
successfully reach and kill infectious agents. As a consequence, these ‘lost’ neutrophils
activated by the burn injury may accumulate and initiate tissue damage inappropriately
in healthy tissues. By administering resolvin D2 to the burned rats, Kurihara et al found
that neutrophil chemotaxis was restored to almost normal. When burned rats received
intravenous lipopolysaccharide 9 days after their burn injury, pre-treatment with
intravenous resolvin D2 improved survival significantly. Similarly, resolvin D2 pre-
treatment increased survival following caecal ligation after burns injury. A shorter
duration of resolvin treatment that was insufficient to normalise neutrophil chemotaxis
did not significantly improve survival in these two models of burns-related sepsis.
Therefore, this study suggests that administering resolvin D2 could improve outcomes
in burns-related sepsis by modulating neutrophil chemotaxis.
Pneumonia and acute lung injury (ALI). The role of resolvin E1 in bacterial
pneumonia and acute lung injury was investigated using a mouse model of aspiration
pneumonia . Mice were administered hydrochloric acid followed by E. coli into a
lung. Resolvin E1, when given intravenously prior to this insult, reduced pulmonary
neutrophil infiltration, enhanced bacterial clearance and decreased levels of pro-
inflammatory cytokines (including IL-1β and IL-6) present in lung tissue homogenates.
Importantly, mice administered resolvin E1 enjoyed increased survival (100% at 3 days,
in comparison to 50% when only 0.9% saline was administered).
Neutrophil apoptosis is known to be a critical event in the resolution of pulmonary
inflammation, and suppression of this process is thought to contribute to the pathology
seen in ARDS and sepsis. In a case-control cohort study of 121 ITU patients with or
without sepsis, the level of neutrophil apoptosis in peripheral venous blood was found
to inversely correlate with the severity of sepsis . The role of resolvin E1 in this
process has been investigated in mouse models of acute lung injury, including an E. coli
pneumonia model and an E. coli peritonitis-associated ALI model . Six hours after
intra-tracheal instillation of E. coli (pneumonia model), intraperitoneal administration of
resolvin E1 enhanced the resolution of E. coli-evoked pneumonia in this mouse model.
In contrast to the control group, mice administered resolvin had lower bronchoalveolar
lavage (BAL) neutrophil counts, higher monocyte/macrophage counts, increased
neutrophil apoptosis, reduced BAL IL-6 levels and less severe pulmonary inflammation
when assessed histologically. When a pan-caspase inhibitor was also added
intraperitoneally, these pro-resolution effects of resolvin were abrogated, suggesting
that neutrophil apoptosis plays a critical role here. In the E. coli peritonitis associated
ALI model, intraperitoneal administration of resolvin E1 also reduced BAL neutrophil
counts and IL-6 levels, increased neutrophil apoptosis and reduced the histological
severity of pneumonia as well as lung MPO content (myeloperoxidase, used as a marker
of neutrophil activity). Importantly, resolvin administration reduced 6 hour mortality
from 70% to 30% in this model.
In terms of a possible mechanism for increased neutrophil apoptosis, in vitro, resolvin
E1 mitigates cellular survival signals generated in response to a number of stimuli
relevant to the pathogenesis of ALI in E. coli pneumonia and sepsis (neutrophil MPO,
serum amyloid A and bacterial CpG DNA). Similarly, 15-epi-lipoxin A4 also has a pro-
apoptotic effect on human neutrophils and in a mouse model of E. coli sepsis induced
lung injury, intravenous lipoxin reduced BAL neutrophil counts and increased caspase-
mediated neutrophil apoptosis .
Herpes simplex virus. As discussed, although inflammation is an essential response to
infection, an excessive response is detrimental and stromal keratitis demonstrates this. It
is an inflammatory lesion of the cornea that is a sequela of ocular HSV infection,
usually appearing one week after primary infection. Importantly, when stromal keratitis
manifests, replicating virus cannot be detected; therefore the initiating virus has been
cleared and the disease is a consequence of non-resolving excessive inflammation. In
mice, ocular HSV infection is a model of stromal keratitis in humans. Topical
administration of resolvin E1 was able to control the immuno-pathological
manifestations of ocular HSV and reduce the severity of stromal keratitis lesions .
The influx of CD4+ T-cells and neutrophils was reduced, as were corneal levels of pro-
inflammatory cytokines known to be involved in the pathogenesis of stromal keratitis.
Levels of the anti-inflammatory cytokine, IL-10, were increased.
Through a screen of the effect of a range of lipid-mediators on the replication of H1N1
Influenza A virus in human lung epithelial cells, protectin D1 was found to significantly
reduce viral replication in vitro . In a model of human severe influenza, virus was
introduced through the intra-tracheal route in mice and protectin D1 levels were found
to be reduced suggesting endogenous production was suppressed by the virus. When
other Influenza A strains were tested, the reduction in protectin levels was found to
inversely correlate with the virulence of the virus strain used. In this same model of
severe influenza, intravenous administration of protectin increased survival.
Administration of resolvin and lipoxin had no effect. Significantly, the protective effect
of protectin was still seen when administered two days after initiation of infection.
Lipoxins, resolvins and protectins are endogenous lipid mediators with a pro-resolution
effect in inflammation. Much work has focussed on their now well recognised role in
allergic airway inflammation [reviewed in 38]. However, an emerging theme is their
importance in the resolution of infection and associated inflammation, and this article
has reviewed emerging data relevant to this. Table I summarises what has been learnt
from animal studies.
The role of lipoxins may vary depending on the specific infection. In a mouse model of
M. tuberculosis infection, transgenic mice unable to produce lipoxin were able to
control the bacteria better with reduced mortality in comparison to wild type, and
expressed IL-12, IFN-γ and NOS2 at higher levels. In contrast, using the same
transgenic mice in T. gondii infection, mortality was higher despite a lower parasitic
burden and this was attributed to excessive cytokine-mediated tissue damage. Beneficial
effects were also seen in a mouse model of Trypanosoma cruzi infection and cerebral
malaria. Topical lipoxin abrogated the tissue and bone damage seen in a rabbit model of
P. gingivalis periodontitis. Therefore, the pro-resolution effects of lipoxin may be
advantageous in protecting the host from the damaging effect of excessive inflammation,
but this benefit may be out-weighed in some situations by permitting un-checked
pathogen replication (as seen in the model of M. tuberculosis). The finding that
administration of lipoxin enhances survival in a mouse model of cerebral malaria
suggests a potential new therapeutic strategy for human cerebral malaria.
The effects of resolvin were investigated in a number of mouse models of systemic
bacterial infection, and were found to enhance phagocytic clearance of bacteria, reduce
neutrophil influx and inflammation severity, promote neutrophil apoptosis and
clearance, modulate neutrophil chemotaxis and importantly, reduce mortality.
Interestingly, resolvin administration also enhanced the antibacterial effect of
ciprofloxacin (in E. coli peritonitis) and vancomycin (in S. aureus skin infection) when
the antimicrobial was administered at a sub-optimal concentration. Topical resolvin
application also reduced the severity of HSV ocular infection in mice. Finally, protectin
was found to increase survival in a mouse model of severe influenza, even when
administered two days after infection.
Given the well-recognised importance of these mediators in allergic airway
inflammation, it is interesting to consider how their regulation may be disturbed in
states of airway inflammation induced by infection, for examples ARDS. Notably,
pulmonary production of protectin was found to be suppressed by highly pathogenic
Influenza A strains . Evidence from Cilloniz et al suggests that lipoxin-mediated
activity is also altered during Influenza A virus infection . Disturbed lipoxin
regulation could have a role in the predisposition towards asthma seen in infants
following RSV bronchiolitis [39, 40], especially when considering the finding that mice
unable to synthesise lipoxin fail to elicit alternative macrophage differentiation, required
for the resolution of RSV disease [15, 16].
If the beneficial effects of these mediators translate from pre-clinical studies into
clinical trials, they represent promising new strategies in the management of infectious
disease. The pro-resolution, anti-inflammatory and antimicrobial-enhancing effects of
resolvins, protectin and possibly lipoxins make these appealing candidates for further
study in humans. From a therapeutic perspective it is important to note that these pro-
resolution mediators enjoy a substantial advantage over steroids for use in the treatment
of infectious inflammation, or other systemic inflammatory states, as they are not
immunosuppressive agents. ‘Aspirin triggered’ lipoxins and resolvins share the pro-
resolution effects of lipoxin A4 and resolvin D1 respectively, and act by the same
intracellular pathways [11, 14, 41]. This effect is unique to aspirin, and is not shared
with non-steroidal anti-inflammatory drugs which do not trigger the biosynthesis of
these mediators. Due to its ability to trigger the production of these pro-resolution
mediators there may be a new role for aspirin in managing the inflammatory sequelae of
Table I: Summary of the role of pro-resolution lipid mediators in animal models of
Downregulation of SOCS2
(required for lipoxin activity)
associated with greater virulence
(required for lipoxin production)
associated with greater lung
Influenza A Mouse 12
Lipoxin contributes to mortality
and mycobacterial load
Lipoxin reduces mortality but
increases parasite load
15-epi-lipoxin A4 reduces
parasitaemia and increases
15-epi-lipoxin A4 increases
Lipoxin reduced leukocyte
infiltration and bone destruction
Mouse Resolvin reduced mortality
Resolvin reduced mortality and
enhanced the antimicrobial
effect of ciprofloxacin
Resolvin enhanced the
antimicrobial effect of
Resolvin reduced mortality
Resolvin reduced histological
severity of pneumonia and
Mouse 32, 34
acute lung injury
Ocular herpes simplex
Mouse Resolvin reduced mortality 34
Mouse Resolvin reduced lesion severity 36
Influenza A Mouse
Protectin reduces viral
replication in vitro and increases
survival in vivo.
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