In this eBook, we have grouped together 16 original contributions which have
addressed the translational potential for therapeutics developed on the conceptual
framework of the resolution of inflammation. The take home message of our effort,
and the efforts of our colleagues who wrote these pieces, is that completely different
drugs can be designed and modelled on the mediators and targets of resolution. By
implementing this 180° shift in the way we plan the drug development programme
(that is by focusing on agonists and/or promoting the actions of pro-resolution
agonists) we can offer a fresh approach to the clinical management of chronic
diseases that affect the modern society. With this series of articles we foresee the
birth of Resolution Pharmacology.
The 16 contributions presented herein confirm the broad relevance of pro-resolving
physio-pharmacology with the description of pro-resolving mechanisms in distinct
diseases, from atherosclerosis and heart infarct, to cystic fibrosis and diabetes. This
testifies on one hand the fundamental role that inflammatory mechanisms play in
virtually all pathological settings and, on the other hand, the great potential that a novel
approach to anti-inflammatory therapy by exploiting resolution mediators and targets
may have. Thus, while there is broad recognition that evidence-based interventions
have transformed cardiovascular, inflammation and endocrine care, new therapies
are still needed for growing numbers of patients with unmet needs. As an example,
an estimated 17 million people world-wide die annually of cardiovascular diseases,
particularly heart attacks and strokes. Cardiovascular diseases occur almost equally
in men and women and are the leading cause of death and morbidity worldwide. It is
estimated that only 1/1,000 compounds entering preclinical testing are then trialled
in man and the actual cost of developing a new therapeutic into clinical practice has
grown exponentially over the past two decades (estimated $1.2B).
Over the last 20 years or more, scientists have appreciated the biology of the
resolution of inflammation, which provides a new paradigm in our understanding
of the inflammatory process with the appreciation of genetic, molecular and cellular
mechanisms that are engaged to actively resolve inflammation. The ‘resolution of
acute inflammation’ is enabled by counter-regulatory checkpoints to terminate the
host reaction while at the same time promoting healing and repair.
The potential of lipid mediators to enact pro-resolving effects in the context of cystic
fibrosis is presented by Recchiuti et al., while Fredman reasons on the potential for these molecules in atherosclerosis. This resonates well with the contributions
from Bäck and colleagues who have focused on pro-resolving receptors to offer
vasculo-protection in intimal hyperplasia and more generally in cardiovascular
disease. On the same vein is the scholar contribution of Leoni and Soehnlein who
focus on heart disease, with Qin et al. presenting the latest findings on the effect
of an Annexin A1-derived peptide in myocardial infarction. Hansen et al. and de
Gaetano et al. bring in the complexity of diabetes and associated morbidity with a
focus on specialised pro-resolving lipid mediators but also introducing the potential
of dietary approaches. As the western diet favours disease, an omega-3 rich diet
can lead to higher availability of lipid mediators to afford tissue protection if not
reverting its pathological status. Docosahexaenoic acid and its bioactive derivatives
are endowed with potent anti-nociceptive properties following bone fracture, as
shown by Zhang et al. The broad relevance of the pharmacological approach
reaches the skin with Resolvin D1 protecting against UV irradiation (Saito et al.).
Reduced skin inflammation is also achieved with an Annexin A1 peptide that impacts
on the outcome of heterologous transplantation (Lacerda et al.). Indeed, modulating
the phenotype of immune cells can provide long lasting beneficial outcomes, as
attained with CDK inhibitors (Cartwright et al.) and PI3K inhibitors in experimental
gout (Galvao et al.). Such an effect is also achieved with a third group of pro-resolving
therapeutics, the melanocortin receptor agonists, with important modulation of
macrophage reactivity (Patruno et al.) with Spana et al., providing new pharmacology
following selective activation of the MC1 receptor. Finally, Hopkin et al. discuss the
potential for targeting immune cell trafficking as a way to control immune mediated
diseases, bringing in not only pro-resolving mediator agonists, but also approaches
to reduce chemo/cytokine gradients or modulating S1P and 11-beta hydroxysteroid
dehydrogenase.
Finally, we wish to highlight that this wealth of science has also bought to the forefront
specific pro-resolving receptors (including FPR2/ALX, GPR32, ChemR23 and MC1),
all G protein coupled receptors that are therefore amenable to pharmacological
exploitation for drug discovery programmes. We see that not only agonists to the
receptors can be developed, some of them modelled on the natural ligands (e.g.
resolvins, lipoxins, Annexin A1-derived peptides or melanocortin peptides), but also
that the creativity of this pharmacology can be attained through biased ligands and
positive allosteric modulators. Deep knowledge of pro-resolving receptor biology and
their cell-specific signalling can accelerate the generation of novel anti-inflammatory
depicted on the resolution of inflammation.
In conclusion, with this eBook, we propose time is ready to exploit the concepts
of resolution and use its targets and mediators for the identification of better drugs
to establish ‘Resolution Pharmacology’. We predict Resolution Pharmacology will
represent an important innovation in the way common diseases will be treated in
the next decades of this millennium.