Therapy based on the resolution of inflammation provides a new paradigm
In higher organisms, the immune system consists of the innate and adaptive (or acquired) systems. The former has evolved to recognise only a limited number of molecules, which are typically different classes of microbes, while the latter recognises many more foreign and highly diverse substances (antigens), which can be characteristics of different microbial species or non-microbial in origin. Deregulation of the immune response cause disease. Currently, many ‘western’ diseases are known to be associated with an uncontrolled inflammatory response that damages tissues and vital organs.
The inflammatory response has classically been divided into two phases: onset and resolution. As was demonstrated in the last century, the onset phase produces a variety of classes of molecules, cytokines, chemokines (chemotactic cytokines) and eicosanoids, which are involved in recruiting different types of leukocytes. Identification of these molecules opened the way to new drugs designed to inhibit or antagonise the biological action and production of local mediators with an important role in the onset and progression of the disease. However, longitudinal studies have shown that, although these drugs are effective in inhibiting inflammation, they also have secondary effects. For instance, non-steroidal anti-inflammatory drugs (NSAIDs) lead to an increase in gastrointestinal bleeding and anti-tumour necrosis factor drugs increase infection rates. These observations showed the clear need for alternatives that would not interfere with the immune system and produce fewer secondary effects, especially in the treatment of chronic diseases.
For many years, it was thought that inflammation ended simply with the weakening of inflammatory signals in the injury or infection site, leading to the withdrawal of the leukocytes and re-establishment of tissue function. Research into mechanisms for ending inflammation showed that arachidonic acid is not just the substrate for the biosynthesis of inflammation ‘onset molecules’ (such as prostaglandins (PG) and leukotrienes), but is also converted into protective anti-inflammatory molecules (lipoxins and prostaglandins with a cyclopentenone structure). Identification of these molecules showed that resolution of inflammation is an active process, coordinated by endogenous mediators that control cell immune responses and which are produced at the injury or infection site.
It is now known that the acute inflammatory response is a coordinated process in which the onset and resolution phases are closely linked: a link has been found between inflammation-initiating eicosanoids (prostaglandins PGE2 and PGD2) and the biosynthesis of lipoxins (involved in the resolution of inflammation); these prostaglandins up-regulate 15-lipoxigenase 1 (15-LOX-1), the enzyme that initiates the lipoxin synthesis pathway. Experimentally, inhibition of prostaglandin biosynthesis by NSAIDs is related to a reduction in the biosynthesis of pro-resolving mediators and delay the end of inflammation.
As well as lipoxins, three super-families of specialised pro-resolving mediators (SPMs) have been identified, which reprogramme the immune response to stop inflammation and re-establish tissue function: docosahexaenoic acid (DHA)-derived resolvins and eicosapentaenoic acid-derived resolvins (RvD and RvE, respectively), and DHA-derived protectins and maresins. Regulation of SPM production is dependent on factors such as time, the organ and certain stimuli; and their concentrations in relation to classic eicosanoids also depend on these factors.
The discovery of SPMs opens the door to developing new pro-resolving drugs that exert their effect on inflammation by using endogenous repair responses, thus they should have fewer secondary effects than currently used drugs (as they would not interfere with the host’s natural immunity). This would also favour the patient’s adherence to treatment.
Furthermore, these findings throw light on the roles of omega-3 fatty acids in controlling acute inflammation, which is not simply through inhibition of inflammatory eicosanoid formation by competition (using the same enzymes in their biosynthesis pathways), but also as precursors to SPMs. Therefore, SPMs can also be used as markers to determine the pharmacodynamics and pharmacokinetics of omega-3 supplements and their ability to influence the host response, in both healthy subjects and those with inflammatory diseases.
Resolution-based therapy provides a new paradigm for tailored medicine, in which supplementation could be used to maintain or boost SPM levels and thus preserve tissue resolution. In the context of disease, SPM-based drugs could be useful in regulating both the local and systemic inflammatory response. Nanomedicines with SPMs or their analogs/mimetics would provide an administration system targeted at the tissue to control inflammation and promote tissue repair and regeneration. The pharmacology of resolution could provide the basis for reprogramming host immunity and accelerating microbial elimination, limiting collateral tissue damage and stimulating tissue regeneration.
Dalli J, Serhan CN. Identification and structure elucidation of the pro-resolving mediators provides novel leads for resolution pharmacology. Br J Pharmacol. 2018 Apr 21. doi: 10.1111/bph.14336. [Epub ahead of print]