Targeted Modulation of Lipid Mediator-Biosynthetic Enzymes as Strategy for Inflammation Resolution Pharmacology

Lipid mediators (LMs) comprise a large variety of signaling molecules that are enzymatically produced from polyunsaturated fatty acids (PUFA) in a wide biosynthetic network. These pivotal mediators regulate all stages of inflammation, from initiation, progression, and maintenance to resolution and regain of tissue homeostasis. While leukotrienes and prostaglandins, produced from arachidonic acid (AA) by the 5-lipoxygenase (LOX) and cyclooxygenase (COX) pathways, respectively, mediate/promote inflammatory reactions and related symptoms, the specialized pro-resolving mediators (SPMs) terminate and resolve inflammation. SPMs encompass mainly the omega-3-PUFA-derived resolvins, protectins, and maresins, which are synthesized by sequential PUFA oxygenation steps, involving primarily 15-LOX-1/2 isoforms, but for some specific SPMs, also the 5-LOX, 12-LOX, COX-2, and cytochrome P450 enzymes mediate one of these oxygenations. Due to their valuable inflammation-resolving features, different strategies have been developed in order to exploit the beneficial functions of SPMs for the intervention with chronic inflammatory diseases. Here, we review the promising strategy of promoting endogenous SPM formation by applying exogenous agents that activate SPM-biosynthetic enzymes, also in combination with omega-3-PUFA supplementation, for resolution pharmacology. Results from pilot clinical trials that confirm the applicability and efficacy of such agents and their combinations in patients suffering from chronic inflammatory disorders are briefly discussed.