Roles, Actions, and Therapeutic Potential of Specialized Pro-resolving Lipid Mediators for the Treatment of Inflammation in Cystic Fibrosis

Abstract

Non-resolving inflammation is the main mechanism of morbidity and mortality among patients suffering from cystic fibrosis (CF), the most common life-threatening human genetic disease. Resolution of inflammation is an active process timely controlled by endogenous specialized pro-resolving lipid mediators (SPMs) produced locally in inflammatory loci to restrain this innate response, prevent further damages to the host, and permit return to homeostasis. Lipoxins, resolvins, protectins, and maresins are SPM derived from polyunsaturated fatty acids that limit excessive leukocyte infiltration and pro-inflammatory signals, stimulate innate microbial killing, and enhance resolution. Their unique chemical structures, receptors, and bioactions are being elucidated. Accruing data indicate that SPMs carry protective functions against unrelenting inflammation and infections in preclinical models and human CF systems. Here, we reviewed their roles and actions in controlling resolution of inflammation, evidence for their impairment in CF, and proofs of principle for their exploitation as innovative, non-immunosuppressive drugs to address inflammation and infections in CF.

Keywords: Pseudomonas aeruginosa; chronic infections; homeostasis; lipid mediator; lung inflammation and fibrosis; macrophages; pharmacology; resolution.

Figure 1

The acute inflammatory response and its ideal outcome: essential steps, mechanisms, and definitions. Injury, infections, or dysregulated homeostasis ignites the acute inflammatory response that is normally a host protective mechanism. The first event in acute inflammation is edema formation, followed by infiltration of PMN, and then monocyte and macrophages that clear PMN leading to resolution, which is essential for ensuring host protection and sparing from tissue damage.

Figure 2

Airway inflammation in CF. A schematic view of the inflammatory response and a few of the secondary pathologic findings in CF airways. Microbial infection (by P. aeruginosa, S. aureus, Non-tuberculosis Mycobacterium, and other pathogens) incites a vigorous, disproportionate inflammatory response. PMNs infiltrate the airway and release proteases and oxidants that damage the airway and chemoattractants that stimulate further neutrophil influx. Although neutrophils and epithelial cells have been most intensely investigated, alterations in endothelial cells (EC), macrophages (MΦ), platelets (PLT), and T lymphocytes also play a pathophysiological role in CF airway non-resolving inflammation. See within text for further details. Not all mediators and cell types implicated in CF are shown.

Figure 3

Biosynthesis and structures of SPM. The biosynthetic pathways leading to lipoxins (A), E-series resolvins (B), SPM derived from DPA (C), D-series resolvins, protectins, and maresins (D) are illustrated. Structures and stereochemistries of some members of each SPM family are shown (see text for further details). AA, arachidonic acid; EPA, eicosapentaenoic acid; DPA, docosapentaenoic acid; DHA, docosahexaenoic acid; LO, lipoxygenase; COX-2, cyclooxygenase 2. MCTRs, maresin conjugate in tissue regeneration; RCTRs, resolvin conjugate in tissue regeneration; PCTRs, protectin conjugate in tissue regeneration. GST/LTC4S, glutathione-S-transferase/leukotriene C₄ synthase.

Figure 4

SPM GPCR and signaling pathways. To date, five specific SPM GPCRs have been identified in human and murine cells: ALX/FPR2, DRV1/GPR32, ERV1/ChemR23, DRV2/GPR18, and GPR37. Binding of SPM to their GPCR regulates cell-specific signaling pathways that ultimately diminish inflammation and enhance resolution. RvE1 also serves as a partial antagonist on leukotriene (LT) B₄ BLT1 receptor to stop PMN infiltration.

Figure 5

Multipronged actions of SPM in CF airway disease. Broad actions of SPM relevant to CF airway disease encompass both anti-inflammation (limitation of further PMN infiltration, reduction in cytokine production, and decrease in lymphocyte, EC, and PLT activation) and pro-resolution (enhancement of MΦ phagocytosis and bacterial clearance, promotion of tissue repair, restoration of epithelial barrier integrity). See within text and references for further details.