Specialized Pro-resolving Mediators and Mimetics: Bridging Resolution Biology and Therapeutic Development.

Abstract

Inflammation is a fundamental host defense mechanism that protects against infection and tissue injury. However, failure to appropriately resolve inflammation contributes to the pathogenesis of numerous pathologies. The discovery of endogenous mediators of inflammation resolution has changed our understanding of the dynamics of self-limiting inflammation. The active resolution of inflammation reflects tightly orchestrated responses to specific mediators including cytokines, peptides, and specialized pro-resolving mediators (SPMs), a superfamily of bioactive lipid mediators that includes the lipoxin, resolvin, protectin, and maresin families of SPMs. These mediators exert their potent pleiotropic immunoregulatory actions at nanomolar concentrations through mechanisms including activation of specific G-protein-coupled receptors (GPCRs), to regulate endothelial activation and promote the cessation of neutrophil recruitment, enhanced macrophage efferocytosis, removal of inflammatory debris, and restoration of tissue homeostasis. The lipoxins (LXs), arachidonate-derived mediators, were the first SPMs described and have emerged as attractive potential therapeutics for acute and chronic inflammatory diseases due to their broad anti-inflammatory and pro-resolving actions. However, translation of these bioactions has proven difficult as a result of their structural limitations and poor chemical stability, making them susceptible to metabolic inactivation. For this reason, the quest to develop structurally protected mimetics has recently gained momentum, and these analogs are designed to preserve receptor-mediated bioactivity while enhancing stability and efficacy. This chapter reviews the biosynthesis, biological functions, and receptor pharmacology of the major SPM families. Furthermore, the therapeutic potential of SPMs and their mimetics is analyzed, summarizing the rationale underpinning the design and preclinical testing of these therapeutic leads across a range of inflammatory and tissue injury models.