Resolution of Inflammation in Asthma
Introduction
Asthma is characterized by increased and chronic airway inflammation.1 Airway sampling by bronchoscopy or sputum analysis most often reveals abundant eosinophils and activated T cells, and lung histology demonstrates airway remodeling with disordered mucosal epithelium.2, 3 Whereas noxious stimuli, including potential allergens, can initiate an acute inflammatory response that is self-limited, nonresolving inflammation is linked to asthma and other chronic inflammatory diseases (reviewed in Ref.4). The overall magnitude and duration of inflammation depends on competing physiologic processes, namely prophlogistic mechanisms that amplify inflammation and endogenous braking programs that control the resolution of inflammation (reviewed in Ref.5). In health, the resolution of inflammation is an active coordinated process that is spatiotemporally controlled by endogenously generated autacoids at sites of inflammation.6 While several classes of mediators participate in resolution, the enzymatic transformations of polyunsaturated fatty acids (PUFAs) to specific proresolving agonists are of particular interest. The discovery that PUFAs are essential dietary constituents7 led to the recognition of their immunoregulatory actions.8 These PUFA-derived mediators display cell type–selective anti-inflammatory, proresolving, antifibrotic, antiangiogenic, and anti-infective actions (reviewed in Ref.5).
This article reviews recent findings on new mechanisms and mediators for resolution of airway inflammation, with a focus on their relevance to asthma.
Section snippets
Resolution of acute inflammation
The acute inflammatory response to inhaled pathogens, particles, and toxins is inherently protective and essential to ultimately restoring the injured airway to its normal physiologic functioning. Acute inflammation is initiated within minutes of recognition of a danger signal, and is generally self-limited, resolving within hours or days. In several conditions that are clinically recognized as lung disease, including asthma, chronic inflammation persists. Somehow, a naturally protective
Polyunsaturated fatty acid metabolism to proresolving mediators
PUFAs are essential nutrients. The ω-6 PUFA, arachidonic acid (AA; 20:4n-6) is incorporated into cellular phospholipids, and on cell activation, specific phospholipase A2 enzymes release AA from the sn-2 fatty acyl bond of phospholipids. AA can then be converted enzymatically by COX to prostaglandins (PGs), by ALOX5 to leukotrienes (LTs) or, by ALOX5 in collaboration with ALOX12 or ALOX15 to lipoxins (LXs).5, 38 The ω-3 PUFAs eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA;
Novel ω-3 fatty acid–derived lipid mediators
Population surveys report that diets rich in ω-3 fatty acids are associated with lower asthma prevalence.89 However, the underlying mechanisms behind this observation remain unclear. Recently, specialized proresolving mediators derived from ω-3 fatty acids were identified in self-limited models of acute inflammation, and were termed resolvins (resolution-phase interaction products).9, 10 Similar to LXs, resolvins can be generated via ALOX5-catalyzed reactions during transcellular biosynthesis
Summary
The resolution of inflammation is an integral and natural part of the physiologic response to tissue injury, infection, and allergen or other noxious stimuli. Resolution is an active process with highly regulated cellular and biochemical events. Several discrete families of natural small molecules have recently been uncovered using a lipidomics approach. Select members are proresolving and stimulate tissue catabasis. These agents include resolvins, protectins and, most recently, maresins.
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Cited by (48)
Inflammation resolution in environmental pulmonary health and morbidity
2022, Toxicology and Applied PharmacologyCitation Excerpt :In asthmatics, apoptotic cell accumulation promotes chronic airway inflammation, excess mucus production, and scarring (Yang et al., 2021; Martinez and Cook, 2021). Reduced LX levels observed in asthmatic lungs could be due to SPM deficiencies in asthma (Yang et al., 2021), either from defective biosynthesis or dysregulated expression of the LXA4 receptor ALX/FPR2 (Levy et al., 2005; Levy et al., 2012; Kazani et al., 2013). Enhanced LT production and reduced LX synthesis is implicated in severe asthma exacerbation (Levy, 2005) and may also result from PUFA deficiency (AA, DHA) in the airway mucosa (Duvall and Levy, 2016).
Altered tissue specialized pro-resolving mediators in chronic rhinosinusitis
2021, Prostaglandins Leukotrienes and Essential Fatty AcidsCitation Excerpt :These endogenously produced autacoids consist of arachidonic acid (AA) derived lipoxins (LXA4, LXB4), eicosapentanoic acid (EPA) derived resolvins (RvE1, RvE2), and docosahexaenoic acid (DHA) derived protectins (PD1), resolvins (RvD1, RvD2, RvD3), and maresins (MaR1, MaR2). Each of these compounds has spatiotemporally controlled and tissue-specific actions, which include halting neutrophil chemotaxis, increasing clearance of apoptotic neutrophils from the inflammatory milieu (efferocytosis), and directing the local chemokine and cytokine environment towards homeostasis [8] Dysregulation of these pathways contributes to the pathogenesis of several chronic disease states such as bronchial asthma [9]. Although earlier studies reported lipoxin deficiency in CRS-AERD [10], a detailed examination of eicosanoid and docosanoid derivatives, particularly SPMs, is lacking in CRS.
Granulocyte-targeted therapies for airway diseases
2020, Pharmacological ResearchCitation Excerpt :Tralokinumab, another anti-IL-13 mAb, also showed inconsistent effects on asthma exacerbation rate in patients with severe, uncontrolled asthma [116] and, similarly to lebrikizumab, was recently been reported to benefit patients with moderate-to-severe atopic dermatitis in a phase III clinical trial [117]. The sustained granulocytic inflammation in asthma suggests that part of asthma pathobiology may be related to an impairment of resolution of inflammation [118]. Resolution of inflammation is an active process coordinated by specialized pro-resolving mediators (SPMs) that leads to termination of inflammation [119].
“Redox lipidomics technology: Looking for a needle in a haystack”
2019, Chemistry and Physics of LipidsCitation Excerpt :Various types of mass-spectrometry (MS) have become, by far, the most sensitive, accurate and quantitative methodology for studies of lipid peroxidation products. Both matrix assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) have been widely used for the analysis of PLs and their oxidized products (Lewis et al., 1990; Levy et al., 2012). Recent technological improvements in mass spectrometric platforms allow for enhanced sensitivity, resolution and scan speed of mass ions.
Funding sources: Dr Levy: National Institutes of Health. Dr Vachier: Med Bio Med. Dr Serhan: National Institutes of Health.
This research was supported in part by the US National Institutes of Health grants AI068084, P01-GM095467, U10-HL109172 and P50-HL107166.
Conflicts of interest: Dr Levy: Consultant for Resolvyx Pharmaceuticals; patents licensed to Bayer Healthcare and Resolvyx; Equity in Resolvyx Pharmaceuticals. Dr Levy's interests were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. Dr Vachier: No conflict of Interest. Dr Serhan is an inventor of patents (resolvins) and proresolving mediators and related compounds assigned to Brigham and Women's Hospital and licensed to Resolvyx Pharmaceuticals. Dr Serhan is a scientific founder of Resolvyx Pharmaceuticals and owns equity in the company. His interests were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies.