Specialized Pro-Resolving Lipid Mediators in Pulmonary Diseases: Molecular and Therapeutic Implications

Abstract

Inflammatory lung diseases (ILDs) represent a global public health crisis characterized by escalating prevalence, significant morbidity, and substantial mortality. In response to the complex immunopathogenic mechanisms driving these conditions, novel pharmacological strategies targeting resolution pathways have emerged throughout the discovery of specialized pro-resolving lipid mediator (SPM; resolvins, maresins, and protectins) dysregulation across the ILD spectra, positioning these endogenous molecules as promising therapeutic candidates for modulating maladaptive inflammation and promoting tissue repair. Over the past decade, this paradigm has catalyzed extensive translational research into SPM-based interventions as precision therapeutics for respiratory inflammation. In asthma, they reduce mucus hypersecretion, bronchial hyperreactivity, and airway inflammation, with prenatal SPM exposure potentially lowering offspring disease risk. In COPD, SPMs attenuate amyloid A-driven inflammation, normalizing cytokine/chemokine imbalances and oxidative stress and mitigating COVID-19-associated cytokine storm, enhancing survival. This review synthesizes SPMs' pharmacotherapeutic mechanisms in ILDs and evaluates current preclinical and clinical evidence.

Keywords: COPD; PUFAs; inflammation; pulmonary diseases; specialized pro-resolving lipid mediators.

Figure 1

Metabolism of specialized pro-resolving lipid mediators. Distribution of different enzymes, intermediaries, and precursors that actively participate in the biosynthesis of SPM during the last stages of inflammation, which develop anti-inflammatory agents that limit tissue damage, PMN infiltration, and elimination of causal agents. ω-3 and ω-6 PUFAs are the starting point for elaborating these pro-resolution molecules. SPM: specialized lipid mediator; PMN: polymorphonuclear cells; ω-3; ω-6; EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid; RvE1: resolvin E1; RvE2: resolvin E2; RvE3: resolvin E3; RvD1: resolvin D1; RvD2: resolvin D2; RvD3: resolvin D3; RvD4: resolvin D4; RvD5: resolvin D5; RvD6: resolvin D6; NPD1: neuroprotectin 1; MaR1: maresin 1; LXA4: lipoxin A4; LXB4: lipoxin B4; LOX: lipoxygenase; COX-2: cyclooxygenase 2; CYPs: cytochromes P450.

Figure 2

Therapeutic mechanisms of specialized pro-resolving lipid mediators in chronic inflammatory lung diseases. SPMs can function as therapeutic agents in various ILDs, such as asthma, COPD, CF, and COVID-19, by intervening in their pathophysiology through various anti-inflammatory and pro-resolution mechanisms: (1) inhibition of the release of pro-inflammatory cytokines and chemokines, (2) changes in the polarization of macrophages from pro-inflammatory phenotype M1 to anti-inflammatory M2, (3) promotion of macrophage-mediated spherocytosis of PMNs, (4) stimulation of phagocytosis of foreign bodies and bacteria, (5) increased synthesis of SPMs by macrophages, (6) inhibition of the activity of mucus-producing glands, (7) increased hydration of pulmonary epithelial tissue, (8) inhibition of fibroblast activity, (9) inhibition of elastase released by neutrophils, (10) regeneration and compensation of pulmonary epithelium, accompanied by a decrease in the apoptosis of lung epithelial cells and a decrease in oxidative stress, (11) promotion of nitric oxide synthesis, and (12) inhibition of transepithelial and transendothelial migration of PMNs. SPMs: specialized lipid mediators; PMN: polymorphonuclear cells; RvE1: resolvin E1; RvD1: resolvin D1; RvD2: resolvin D2; RvD3: resolvin D3; PD1: protectin 1; MaR1: maresin 1; LXA4: lipoxin A4; OS: oxidative stress; NO: nitric oxide; ASL: mucociliary clearing; ILD: inflammatory lung disease; COPD: chronic obstructive pulmonary disease; CF: cystic fibrosis.