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  • Review Article
  • Published:

Inflammatory Resolution: new opportunities for drug discovery

Nature Reviews Drug Discovery volume 3, pages 401–416 (2004)Cite this article

Key Points

  • Much of the current treatment for chronic inflammatory diseases is based on the inhibition of mediators that drive acute inflammation.

  • This strategy has never fully cured inflammation-based disease processes, serving only to deal with the symptoms of the conditions. Invariably, established therapeutics also inhibited essential physiological processes, resulting in unsavoury side effects or, in some recent advancements, leaving the patient open to opportunistic infection. So, an improvement in the efficacy of existing medicines with greater tolerability is welcome.

  • In addition to factors that drive inflammation, we are now beginning to understand that there are a whole range of mediators, receptors and intracellular signalling events that are important and have an active role in orchestrating acute inflammatory resolution.

  • We are beginning to realize that in addition to halting the trafficking of leukocytes to an inflamed site, inflammatory cells die in a highly specialized manner and are subsequently cleared in a way that is particularly conducive to the host's well-being. Successful resolution will limit tissue damage and, arguably, reduce the propensity for the development of chronic inflammation.

  • As pro-resolution mediators show potent anti-inflammatory effects in vitro and show great promise in the treatment of experimental inflammatory diseases in vivo, perhaps we can now take a closer look at what switches off acute inflammation normally and develop drugs based on their mode of action to treat chronic, non-resolving inflammatory diseases. It is hoped that novel compounds based on the mechanism of action of a given pro-resolving pathway will be modulatory in nature, with fewer side effects compared to existing anti-inflammatories.

Abstract

Treatment of inflammatory diseases today is largely based on interrupting the synthesis or action of mediators that drive the host's response to injury. Non-steroidal anti-inflammatories, steroids and antihistamines, for instance, were developed on this basis. Although such small-molecule inhibitors have provided the main treatment for inflammatory arthropathies and asthma, they are not without their shortcomings. This review offers an alternative approach to the development of novel therapeutics based on the endogenous mediators and mechanisms that switch off acute inflammation and bring about its resolution. It is thought that this strategy will open up new avenues for the future management of inflammation-based diseases.

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Figure 1: Scheme of events depicting the various consequences to acute inflammation.
Figure 2: Arachidonic metabolism by COX, as well as the LOX and cytochrome p450 family of enzymes.
Figure 3: Biosynthesis of LXs occurs through three distinct biosynthetic pathways.
Figure 4: Synthesis of DHA- and EPA-derived eicosanoid resolvins.
Figure 5: The profile of NF-κB subunit binding from onset to resolution in acute inflammation.
Figure 6: A general schematic summarizing the mediators and mechanisms that drive and switch off acute innate inflammation.

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Authors and Affiliations

  1. William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK

    Derek W. Gilroy & Mauro Perretti

  2. Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0636, California, USA

    Toby Lawrence

  3. Respiratory Medicine Unit, Centre for Inflammation Research, University of Edinburgh Medical School, Teviot Place, Edinburgh, EH8 9AG, UK

    Adriano G. Rossi

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DATABASES

LocusLink

ALXR

annexin-1

BAX

BCL2

BCL3

CD40L

CD44

COX2

FASR

FOS

FPRL2

IL-1β

IL-12

JUN

NF-κB

p50

p53

PPARγ

RELA

TNF-α

OMIM

Alzheimer's disease

asthma

atopic dermatitis

Huntingdon's disease

multiple sclerosis

Parkinson's disease

rheumatoid arthritis

Glossary

VASCULAR LEAKAGE

The process of the escape of plasma and plasma proteins, along with white blood cells, from the vessel is known as exudation. This inflammatory exudate accounts for an increase in the volume of interstitial fluid (oedema) and tissue swelling at the local site of injury.

NON-PHLOGISTIC

Non-inflammatory. This term is used to describe the clearance of leukocytes in a manner that does not elicit an inflammatory response.

NF-κB

(Nuclear factor of κB). A group of sequence-specific transcription factors that are best known as key regulators of the innate and adaptive inflammatory responses, cell survival and ancogenesis. In mammals, NF-κB consists of five structurally related and functionally conserved proteins: RELA (p65), RELB, c-REL, NF-κB1 (p105 and p50) and NF-κB2 (p100 and p52).

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS

(PPARs). Members of the nuclear receptor family that regulate the transcription of genes involved in lipid and lipoprotein metabolism, glucose and energy homeostasis, as well as cellular differentiation. They consist of three isotypes: alpha (NR1C1), gamma (NR1C3) and beta/delta (NRC1C2), with a differential tissue distribution.

SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION

Signal transducers and activators of transcription (STAT) proteins are intracellular effector molecules of cytokine-modulated signalling.

POLYMORPHONUCLEAR LEUKOCYTES

(PMNs). Discovered by Paul Ehrlich who used contemporary fixing and staining techniques to identify the lobulated nucleus and the granules that typify cells that we now classify as eosinophils, basophils and neutrophils. In the context of this review, PMNs refer to neutrophils.

DELAYED-TYPE HYPERSENSITIVITY

(DTH). A delayed-type hypersensitivity or type IV hypersensitivity is mediated by T lymphocytes and not by antibody–antigen complexes (arthus or type III hypersensitivity). Typically, this response occurs 24–72 hours after the sensitized host is exposed to the offending antigen. For example, a DTH reaction might be set up experimentally by sensitizing to methylated bovine serum albumin in Freund's complete adjuvant and challenging 12 days later with the same antigen.

TH1

The TH1/TH2 hypothesis came to prominence in the late 1980s, indicating that mouse T-helper (TH) cells broadly express differing cytokine profiles. Whereas T-helper 1 (TH1) cells secrete IFN-γ and TNF-α; TH2 cells secrete IL-4, IL-5 and IL-13. In addition, TH3 and regulatory CD25+CD4+ T cells exist that produce TGF-β and IL-10, respectively.

BILIVERDIN and BILIRUBIN

Haem catabolites with anti-inflammatory properties due to scavenging of free radicals.

AIR-POUCH MODEL

The inflation of an air pouch on the dorsum of mice or rats allows for the introduction of inflammatory stimuli to examine either innate or adaptive immune responses.

cAMP

(Cyclic adenosine monophosphate). A second messenger system with inflammo-modulatory properties.

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Gilroy, D., Lawrence, T., Perretti, M. et al. Inflammatory Resolution: new opportunities for drug discovery. Nat Rev Drug Discov 3, 401–416 (2004). https://doi.org/10.1038/nrd1383

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