Eicosanoids and Inflammation: A delicate balance of Pro-Inflammatory and Pro-Resolving mediators

Inflammation represents a fundamental biological process essential for host defense and tissue integrity. However, its dysregulation, frequently characterized by a failure of active resolution, underpins a vast array of chronic pathologies. Central to this intricate process is the superfamily of eicosanoids, which are potent bioactive lipid mediators derived from 20-carbon polyunsaturated fatty acids (PUFAs). Historically, specific eicosanoids, such as prostaglandins (PGs) and leukotrienes (LTs), were regarded primarily as pro-inflammatory agents purported to be responsible for mediating vasodilation, leukocyte trafficking, nociception, and pyrexia. Consequently, therapeutic interventions like non-steroidal anti-inflammatory drugs (NSAIDs) concentrated on inhibiting their production via cyclooxygenase (COX). A significant paradigm shift posited that resolution is not passive decay but an active process orchestrated by specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins. While pharmacological reports suggested these mediators direct inflammatory cessation via specific receptors, recent independent investigations have raised salient questions regarding their endogenous biosynthesis, receptor validation, and detection. This review details established biosynthetic mechanisms (COX, LOX, CYP) and contrasts classical pro-inflammatory signaling with proposed SPM actions. Crucially, a balanced perspective on the extant scientific debate is furnished, addressing the empirical challenges in reproducing SPM receptor activation—and the novel alternative mechanisms now being proposed—as well as the analytical hurdles impending their quantification. Finally, an examination is conducted regarding how a defined imbalance in these opposing mediator pathways contributes to the pathophysiology of diverse conditions, followed by a discussion of emerging therapeutic strategies that have evolved from solely inflammation-inhibition to the active promotion of its resolution.