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The FASEB Journal • Silver Anniversary Review
The resolution of inflammation: the devil in the flask
and in the details
Charles N. Serhan1
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology,
Perioperative, and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women’s Hospital
and Harvard Medical School, Boston, Massachusetts, USA
AQ:1, Key Words:
AQ:2
In looking at the past, present and then to the future
of this field of inflammation research, as in many facets
of history and human experience, is it possible to
accurately project the future of a scientific area? This is
a particular challenge since many of the new and
exciting discoveries in the biomedical sciences are, for the
most part, serendipitous (1–3). As a result, our knowledge
of pathophysiologic processes is nonlinear with time,
entering as rather sporadic leaps in our appreciation of
the complexities of human health and a given disease
process. Certainly, from the relatively recent change in
the concept of resolution as a passive means to complete
an acute inflammatory response to the discovery and role
of novel autacoid biosynthetic pathways for potent active
mediators and mechanisms of resolution that can be used
to stimulate the return to homeostasis is a 180° change in
concepts and potential for new treatments in the past 25
yr (4 – 6). The prevailing notion in treating inflammation
likely began with Hippocrates and the use of salicylates
present in willow bark to knowledge of the cellular events
in the acute inflammatory response and the ability of
aspirin to inhibit key mediators of inflammation (7).
Aspirin (a derivative of salicylates) proved to be one of the
more commercially successful drugs. The total organic
synthesis of aspirin was accomplished in the 1850s, and
the drug was introduced into the market in the early
1900s. Therefore, many therapeutic agents were introduced with the goal of mimicking aspirin’s mechanism of
action, namely, inhibiting cyclooxygenases and prostaglandin biosynthesis (8, 9). The notion of blocking proinflammatory mediators, enzymes, and pathways, whether
by small-molecule inhibitors, receptor antagonists, or neutralizing antibodies, is a concept that prevailed in the past
century and is still in wide use today. Nonetheless, new
evidence has emerged that points to an unobvious and
new direction, namely, stimulating resolution and the
return of the tissue to homeostasis with endogenous
chemical mediators of resolution.
For this Silver Anniversary edition of The FASEB
Journal, I shall take a brief tour of our understanding
and the changes in concepts that have evolved around
the process of resolution of acute inflammation and its
implications for human disease as well as the opportu0892-6638/11/0025-0001 © FASEB
nities that now open in terms of novel therapeutics and
treatments.
It is appropriate to start with two definitions from
Taber’s Cyclopedic Medical Dictionary (10):
resolution 1. Decomposition; absorption or breaking
down of the products of inflammation. 2. Cessation of
inflammation without suppuration. The return to normal.
resolvent 1. Promoting disappearance of inflammation. 2. That which causes dispersion of inflammation.
These two definitions evolved since ancient times in
our appreciation of disease and injury at the gross and
tissue levels and, most important, the effect of phagocytic cells in inflamed tissues as viewed from tissue
histology by pathologists (Table 1). As early as the T1
ancient medical encyclopedias, as recorded in several
chapters of the Canon of Medicine in the 11th century CE
and translated to Europe around the 12th century (11),
the notion of “resolvent mollificants” for the treatment
of inflammation was clearly evident. However, what a
resolvent constituted was not clear, nor was its molecular form known. As indicated by the definition in
Taber’s, a resolvent promotes or causes the dispersion of
inflammation. In the present day, the first notions of an
agonist stimulating processes that can return the inflamed tissues to homeostasis arise from the identification and structural elucidation of potent mediators
termed resolvins, or resolution-phase interaction products (12–14).
In the timeline of literature that gives rise to our
appreciation of resolution of self-limited acute inflammation as an active biochemical process (Table 1), by
1979, Robbins and Cotran (15), in the second edition
of their famous textbook of pathology, provided a
schematic illustration (redrawn in Fig. 1) that depicts F1
inflammatory exudate resolved vs. exudate reorganization. They also introduced the notion of precise cellular events involved in resolution vs. the path to chronic
inflammation. Yet, at the time, these events were considered to be passive, in that the initial leukocyte
stimulus, the chemoattractant, was thought to dissipate,
1
Correspondence: Harvard Institutes of Medicine, 77 Ave.
Louis Pasteur, HIM 829, Boston, MA 02115, USA. E-mail:
[email protected]
doi: 10.1096/fj.11-0502ufm
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TABLE 1. Timeline for resolution of inflammation and regeneration link to ␻-3 PUFAs
Year
Discovery
11th century; translated to the
West in the 12th century
1979
1988
1994
1996
1999
1999
2000
2000
2001
2002
2002
2006
2007
2009
Reference
Resolvent mollificants for treating “inflammatory foci”
11
Inflammatory exudate resolved vs. exudate organized
Cellular events in resolution of inflammation; macrophage clearing of
dead PMN cells and debris
Complete resolution as an outcome of acute inflammation; chronic
inflammation as a failure to resolve
Differential signals for chemical mediators
Lipoxins are a stop signal for PMN recruitment and nonphlogistic
stimuli for monocytes
COX-2 may have anti-inflammatory properties
Glucocorticoids promote nonphlogistic phagocytosis of apoptotic
leukocytes
Lipoxins stimulate macrophage phagocytosis of apoptotic PMN
Discovery of resolvin E1 and the link to ␻-3 PUFAs; resolution is a
biosynthetically active process
Mediator eicosanoid class switching from prostaglandins and
leukotrienes to lipoxins in resolution
Discovery of the resolvins, protectins, and their aspirin-triggered forms
Peptide mediators in resolution; annexin activation of ALX/FPR-2
receptor and enhanced macrophage phagocytosis
Efferocytosis of apoptotic PMN cells; removal of macrophages; failure
to chronicity
Consensus report on resolution of inflammation: definitions and terms
Report of the first patients treated with a resolvin, an agonist to
stimulate and treat inflammation
15
19–21
simply burn out, or simply dilute the signal that would
then lead to decreased infiltration or stopping of the
leukocyte recruitment to the infected or injured tissues
22, 26
32
40
75
35, 52, 53, 76
12
36
13
52, 53, 76
49
6
47
(16). Professor Ramzi Cotran (17) was first to recognize
that the cells of the vessel wall, the endothelium, were
activated, a process, along with neutrophil [polymor-
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Figure 1. Inflammation, repair, and resolution in 1979.
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F2
phonuclear (PMN) cell] activation (18), critical to
mounting a well-integrated acute inflammatory response. The cellular events in the resolution of inflammation were further advanced from the studies of
Savill, Henson, and Haslett in 1989 (19, 20), with the
recognition that macrophages (the big eaters), which
were already known to clear up tissue and cellular
debris (21), advanced to uptake dead apoptotic PMN
cells and cellular debris as part of the resolution
sequence of events. Complete resolution as an ideal
outcome of acute inflammation and the notion that
chronic inflammation can evolve as a failure to resolve
recurring bouts of acute inflammation emerged in
1994 in the fifth edition of the Cotran et al. (22)
textbook. This set the stage for these cellular pictures
and events in the resolution of inflammation when
considering the context of an acute inflammatory response.
A little more than 25 yr ago, Sune Bergström, Bengt
Samuelsson, and Sir John Vane each shook the hand of
the Swedish king as they received their Nobel Prize
medals in December 1982, for their work on the
discovery and biosynthesis of the prostaglandins and on
the action of aspirin. Prostaglandins play important
roles in many physiological responses, e.g., renal function, hemodynamics, reproduction, and, notably, inflammation, which was already recognized at the time
(9, 23). The notion of chemical mediators was also
already brewing in the air from the studies of von Euler
on histamine (24). Considering inflammation, it was
clear at that time that many chemical signals are
involved in the acute inflammatory response and the
usual associated collateral tissue damage: for example,
the leakage of reactive oxygen species from the primary
phagocytic vacuole to cause tissue destruction, the
release of lysosomal enzymes, etc. (18), and the potent
actions of the lipid-derived platelet-activating factor
(PAF), arachidonic acid and its conversion to prostaglandins and leukotrienes, as well as complement, and
the cytokines (25). The structure-function and biosynthesis of the eicosanoids, as carried out by Professor
Bengt Samuelsson and colleagues (23), in many respects led our current understanding and appreciation
of structure-activity relationships and what we today call
chemical biology, as well as metabolomics, much of
which emerged from the study of these very potent
short-lived arachidonate-derived local-acting autacoids
like prostacyclin and thromboxane (23).
Following the award ceremony during the week of
the Nobel Fest in December, there is a splendid Nobel
dinner at which special utensils and glassware are used,
including special Nobel schnapps flasks by Orrefors.
The design was beautifully sculpted by Gunnar Cyrén
and introduced by the official glass artisans of the King
of Sweden. The base of these flasks, pictured in Fig. 2,
portrays the devil; hence, at the end of this momentous
celebration, there is a thoughtful reminder of the
alcohol and its power of intoxication, and the devil at
the bottom of the glass serves as a caution. This image
also reminds us that the devil is in the details in
RESOLUTION OF INFLAMMATION
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Figure 2. Devil in the flask: 3 devil flasks from Orrefors,
designed and sculpted by Gunnar Cyrén. These schnapps
flasks are used at the Nobel dinner in Stockholm during the
Nobel Festival each year.
studying inflammation and its complex resolution
mechanisms. The key to controlling inflammation, as
needed to treat inflammatory diseases, lies in appreciating the molecules and mechanisms in resolution
toward the structure-function or the molecular details
in resolution of acute inflammation–the termination of
this protective response of the host.
CHEMICAL MEDIATORS OF RESOLUTION
In the early 1990s, it became clear that differential
formation, activation, and inactivation of local autacoids, such as the lipoxins (LXs; refs. 4, 26) act on both
human neutrophils and monocytes but show differential cell-type-specific actions on these cells and are
inactivated locally by monocytes (27). Although the
LXs were born in Stockholm in the early 1980s in the
Samuelsson laboratory (28), it took some time to
uncover that their functions are anti-inflammatory and
to demonstrate their potent endogenous actions, stopping neutrophil infiltration and hence local stop signals (29 –31). In these findings from many laboratories
around the world (31), it became clear that the LXs are
potent stimuli for monocytes and their nonphlogistic
recruitment, i.e., they do not stimulate the release of
reactive oxygen species or proinflammatory signals.
This differential action on neutrophils vs. monocytes
paved the way for LXs to transition their actions from
inflammation to repair (32, 33).
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Introduction of stable analogs also permitted critical
experiments that demonstrated for the first time that
LXs could block PMN cell recruitment, regulate inflammation, reduce fibrosis (4, 29, 30, 34), and also stimulate phagocytosis of apoptotic PMN cells by macrophages (35). These findings further fortified the notion
that LXs could play an important role in resolving
mechanisms (26). Notably, LXs clearly display unique
actions and do not function like PGE2 in the inflammatory response and its resolution, in that LXs accelerate resolution, as when and where in their biosynthesis proved critical in identifying their functions, since
they are produced locally in the resolution phase in
exudates (29, 36).
Also, Adriano Rossi and D. A. Sawatzky (37) established that the widely used anti-inflammatories, glucocorticoids, also stimulate macrophages to clear apoptotic leukocytes. Much of the community interested in
controlling inflammation was focused at the time on
making better aspirins, superaspirins that could inhibit
the newly uncovered inducible cyclooxygenase denoted
COX-2 (8). Unfortunately, this also proved to be a
challenging target (38, 39), giving rise to complications
apparent with prolonged use of selective COX-2 inhibitors. More important, it became evident that COX-2
(the “bad COX” responsible for the proinflammatory
eicosanoids; ref. 8) also plays an important role in
endogenous anti-inflammation (40).
These findings created a constellation of data sets
from several laboratories that could be stitched together in a network connection, given the clarity of
hindsight. Together, they set the stage for the discovery
of the first resolvin, RvE1, and its link to precursor
polyunsaturated fatty acids (PUFAs) using an unbiased
LC-MS/MS approach (12). This observation also led to
the notion that resolution is a biosynthetically active
process and that mediators regulate the cellular traffic
of resolution. In parallel investigations, leukocyte trafficking and lipid mediator profiling using LC-MS/MSbased lipidomics led to identification of mediator class
switching (36), from the initiation phase evoked by
prostaglandins and leukotrienes, to LXs in the resolution phase, to the discovery of potent mediators that
stop neutrophil activation and are proresolving, in that
they stimulate macrophage uptake of apoptotic cells
and neutrophils as well as microbes and enhance their
destruction (13, 41). In addition to the E series of
resolvins, DHA, the other major n-3 PUFA in marine
oils, is a precursor to D-series resolvins and, in neural
systems, to neuroprotectins, e.g., neuroprotectin D1
(NPD1; refs. 42, 43). This was accompanied by the
structural elucidation and identification of aspirintriggered epimeric forms of the protectins and resolvins (13, 44) and introduction of stable analogs of
these compounds that share the very unique mechanism of resolvins and proresolving mediators (45):
namely, dampening neutrophilic infiltration without
being immunosuppressive, actually enhancing microbial killing (46), and stimulating macrophages to remove apoptotic cells and microbes (44). Most recently,
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the agonist resolvin was introduced to stimulate resolution of inflammation in humans for the treatment of
ocular inflammation (47). Hopefully, this first study of
the effect of resolvins in humans will open the door to
future studies of agents that can stimulate the resolution mechanisms and resolve acute inflammation as
well as disperse chronic inflammation to alleviate human diseases where uncontrolled inflammation underlies part of the pathophysiology.
The birth of aspirin-triggered lipid mediators (12, 13,
48), the understanding of catabasis as the return from
the battle of disease to tissue homeostasis (14), and the
recognition of the important role of macrophages in
efferocytosis (49 –51) at present provide many new
opportunities to appreciate the cellular and molecular events in resolution and the identification of the
first chemical mediators or signals of resolution (4).
Treatment with glucocorticosteroid proved to activate the annexin system with the production of
endogenous anti-inflammatory peptide ligands that
activate the LX receptor on leukocytes to stop neutrophil recruitment and neutrophil-mediated tissue
damage (52). Next, Perretti and colleagues demonstrated that annexin-derived peptide also enhances
macrophage uptake of apoptotic neutrophils (53) as
do the LXs and their aspirin-triggered endogenous
epimers (52). Hence, peptides can also be proresolving mediators (Table 1).
The present and ever-expanding universe of proinflammatory mediators includes the many cytokines and
chemokines present and the inflammasome (for a
recent review, see refs. 54, 55). The importance of
pattern-recognition receptors (56) and “eat-me” signals, e.g., apoptotic phosphatidylserine (57), inform us
that there are likely to be as many players and local
mediators in resolution to homeostasis as there are
within the initiation process. This would not be surprising. But what is of special interest is that activation of
resolution cascades enhances the resolution response and appears to evoke a classic feed-forward
mechanism (58).
The universe of lipids encompasses more than PUFAs,
and the advances in software and computers enabling
rapid mass spectrometry without requiring the derivatization of samples open the possibility to categorize
many known and new lipids, an activity currently taken
by the Lipid Metabolites and Pathways Strategy (MAPS)
program, which links sphingolipids, PUFAs, lipid
mediators, cholesterol, sterols and many others (59).
Studying self-limited inflammation-resolution and structural elucidation of novel lipid mediators and their structure-activity relationships presently helped to define the
novel biological property, namely, a proresolving mediator and process. Using unbiased LC-MS/MS techniques
with self-limited inflammatory exudates and a systems
approach also affirmed that resolvins are biosynthesized
from endogenous ␻-3 essential fatty acids (44). They are
enhanced in transgenic fat-1-overexpressing mice (60)
and exert potent actions that stimulate resolution and
limit further recruitment of inflammatory cells, such as
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neutrophils. These opened an even wider landscape with
links to nutrition, where we had already known that there
are beneficial actions of ␻-3 essential fatty acids (61– 63);
however, the mechanism and effect of these at the cellular
and molecular levels in inflammatory diseases were not
clear and were subject to debate (62) because of a lack of
structure-activity relationship from the ␻-3 fatty acids. The
new relationship between the ␻-3 fatty acids and resolution of inflammation suggests that micronutrition via
local edema feeds the resolution process and has a direct
effect on the time course, duration and evolution of
inflammation and likely on its failure, in the case of
malnutrition of the resolving exudate (64).
The late Professor Guido Majno, a founding father of
molecular pathology (65), in his textbook (16), forged
the future for LXs and resolvins when he wrote:
Overall, the mediators at work in the various phases of
wound healing overlap with those of acute and chronic
inflammation and fibrosis. As regards the antiinflammatory eicosanoids found in the resolving phase of inflammation, lipoxins, and resolvins, they have not yet been studied
in wounds, but it would be surprising if they did not take
part in the noble enterprise of wound healing. (16)
His insight and prophecy proved to be the case in that
LXs, protectin D1, and D-series resolvins are shown to
reduce tissue injury (66, 67) and prevent fibrosis (68).
These are exciting possibilities and open up many
opportunities for considering novel therapeutic approaches for treating inflammation and inflammationassociated diseases (see consensus report, ref. 6, and
ref. 37).
FUTURE RESOLUTION AT 25 yr AND BEYOND
It is a certain bet that, in the 25 yr ahead, more
cellular and molecular details in self-limited inflammation and its resolution will be discovered. The
devil is in the details of resolution of inflammation
and the return of inflamed tissues to homeostasis; the
structure-function of resolution mechanisms will permit how we can use these new molecules and relations to maintain health and prevent and treat diseases.
Rigorous attention to cellular-molecular definitions,
precise structure-activity relationships, and the use of
tissue resolution indices (6, 69) can help to propel this
area forward and open up a new appreciation of
inflammation-associated disease mechanisms and potentially opportunities for designer therapeutics; for
example, recent results from Prof. Derek Gilroy and
colleagues (70) that identified those human subjects
who are “early resolvers” and those who are “delayed
resolvers.” This landmark study defines the resolving
dynamics of the human phenotypes in healthy subjects
(70); in the 25 yr ahead, they will surely be interrogated
at the molecular levels. There is also the glimmer of
emerging evidence from clinical trials that designer
resolvins and mimetics of this natural process (47, 71)
will be useful in making analogs (72) of these potent
RESOLUTION OF INFLAMMATION
mediators, which also extend from inflammation into
direct action in resolving pain, both peripherally and
centrally (73).
Some steps need to be taken that will surely lead to
discovery, particularly those that will enable evidencebased practices for individualized optimal maintenance
of the immune system, the neuronal system, and the
related axis. These will come into play when this field
addresses the question of the minimum daily amount of
PUFAs (both n-6 and n-3) required for timely resolution of inflammatory insults. Clinicians will be able to
routinely profile the precursor ␻-3 fatty acids and
PUFAs in the blood and tissues of individuals to get a
“dipstick” of these essential nutrients. The transformation of these PUFAs, including the ␻-3- and arachidonate-derived mediators (e.g., eicosanoids, D-series resolvins, and maresins) and their metabolomics might
be detailed on an individual basis for blood chemistries
in the near future as the clinical pathology/wellness
report. Only widescale implementation is needed, for
the methods are already in the hands of researchers.
We should then be able to personalize the levels of
essential PUFAs to the precise amounts needed by each
individual and each site of utilization in men and
women, old and young. We may then prescribe, with
the knowledge of evidence-based medicine, the needed
proresolving precursors and agents tailored to direct
use in vivo.
In the 19th and 20th centuries, inhibiting production of inflammatory mediators prevailed as a mode
of treatment. In the next 25 yr, perhaps the field will
grow to use agonists of resolution, and in this way
return to the concept from the 11th century Canon of
Medicine, which appears to be a “back to the future”
scenario for stimulating resolution of inflammation
as a treatment modality (Table 1) and pus bonum et
laudabile (good and laudable pus; ref. 17). Hence, in AQ: 3
2010, we appreciate the good molecules also present
in pus and evolving exudates that together constitute
a new genus of specialized proresolving mediators
(Fig. 3). It is difficult to quickly turn around a F3
battleship that has momentum. Nonetheless, along
these lines, nutraceuticals, such as PUFA derivatives
and/or related mimetics of resolution autacoids,
could be prescribed either alone or with specific
resolvins and/or combined with other classic antiinflammatories, e.g., NSAIDs, steroids, etc. Designer
resolvins might be used alone or together with other
anti-inflammatory or proresolving therapies.
It is equally likely that the mechanisms of resolution can also be targets of impairment, genetic losses,
or markers of aberrant resolvin production. Such
conditions or defects in resolution might be observed
in the future as molecular defects leading to many
chronic inflammatory diseases. The loss of a resolvin
receptor on leukocytes, for example, may lead to
uncontrolled inflammation, as we have reported that
overexpression of a receptor for a proresolving mediator enhances resolution, shortening the resolution interval and the time required to return to
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Figure 3. Chemical mediators of inflammation and the resolution mediator metabolome in 2010.
homeostasis (74). These are wishful thoughts, looking 25 yr past and further, as to where the resolution
trajectory starts, and may take us in the future, for
resolution mechanisms in terms of the molecules,
mediators, and cellular and molecular mechanisms
and their likely effects in resolution pharmacology
and the treatment of human diseases. That cool
devil!
7.
8.
9.
10.
The author is an inventor on patents assigned to
Brigham and Women’s Hospital and Partners HealthCare
(Boston, MA, USA) on the composition of matter, uses,
and clinical development of anti-inflammatory and proresolving lipid mediators. These are licensed for clinical
development. The author retains founder stock in Resolvyx
Pharmaceuticals.
11.
12.
13.
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