Systems approach with inflammatory exudates uncovers novel anti-inflammatory and pro-resolving mediators

Abstract

Using a systems approach to mine spontaneously resolving inflammatory exudates, novel families of lipid- derived mediators were identified in animal systems that control both the duration and magnitude of acute inflammation. These new families were coined with the resolvins and protectins because they possess potent bioactions and novel chemical structures. The mapping of these new resolution circuits has already provided new avenues for appreciating the molecular basis of many inflammatory diseases. This presentation/mini review gives recent advances from our studies on resolvin and protectin biosynthesis and the actions of these novel mediators. These previously unappreciated families of lipid-derived mediators were originally isolated from murine models of acute inflammation captured during the natural spontaneous resolution phase. They are biosynthesized from omega-3 fatty acids and possess potent anti-inflammatory, pro-resolving and anti-fibrotic in vivo actions. These new families of endogenous pro-resolving and anti-inflammatory agonists were also used as biotemplates to design potent mimetics/analogs which were used to confirm each of their structures and specific functions. Moreover, together the identification of these mediators indicate that resolution is an active process at the tissue level in vivo as well as constitute a new genus of anti-inflammatories with a previously unknown pro-resolving mechanism of action.

Figure 1

Lipid mediators in acute inflammation. In response to injury or infection, the acute inflammatory reaction is normally a protective mechanism, initiated by neutrophils summoned to the site to engulf and destroy invading microbes. In this process, neutrophil-derived pro-inflammatory mediators, such as leukotrienes and prostaglandins, and the unintentional release of hydrolytic enzymes and reactive oxygen and free radicals can enhance this process potentially leading to chronic inflammation. At contained exudate sites, within the resolution phase neutrophils promote resolution when they change phenotype (lower panel) to generate protective mediators that are derived from polyunsaturated fatty acids (PUFA).

Figure 2

Biosynthesis of specialized mediators in resolution of acute inflammation. Local mediators include the lipoxins (LX) derived from arachidonic acid (AA); resolvins derived from omega-3 PUFAs eicosapentaenoic acid (EPA; resolvins E series) and docosahexaenoic acid (DHA; resolvins D series); and protectins enzymatically derived from DHA. The structures of each of these key mediators have been confirmed by total organic synthesis (see text for details).