Elsevier

European Journal of Pharmacology

Volume 785, 15 August 2016, Pages 144-155
European Journal of Pharmacology

DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation

https://doi.org/10.1016/j.ejphar.2015.11.001Get rights and content

Abstract

Essential fatty acids can serve as important regulators of inflammation. A new window into mechanisms for the resolution of inflammation was opened with the identification and structural elucidation of mediators derived from these fatty acids with pro-resolving capacity. Inflammation is necessary to ensure the continued health of the organism after an insult or injury; however, unrestrained inflammation can lead to injury “from within” and chronic changes that may prove both morbid and fatal. The resolution phase of inflammation, once thought to be a passive event, is now known to be a highly regulated, active, and complex program that terminates the inflammatory response once the threat has been contained. Specialized pro-resolving mediators (SPMs) are biosynthesized from omega-3 essential fatty acids to resolvins, protectins, and maresins and from omega-6 fatty acids to lipoxins. Through cell-specific actions mediated through select receptors, these SPMs are potent regulators of neutrophil infiltration, cytokine and chemokine production, and clearance of apoptotic neutrophils by macrophages, promoting a return to tissue homeostasis. This process appears to be defective in several common human lung diseases, such as asthma and COPD, which are characterized by chronic unrestrained inflammation and significant associated morbidity. Here, we highlight translational research in animal models of disease and with human subjects that sheds light on this rapidly evolving area of science and review the molecular and cellular components of the resolution of lung inflammation.

Introduction

The hallmarks of acute inflammation include specific cellular events, including increased permeability of the endothelium and epithelium, infiltration of polymorphonuclear leukocytes, inflammatory macrophages, and lymphocytes to sites of infection or injury, and subsequent tissue edema (Cotran and Collins, 2009). The cellular events of resolution oppose inflammation and in a process known as catabasis return the host tissues to a non-inflammatory state (Serhan et al., 2004). Barrier integrity is restored and the permeability of endothelium and epithelium is reduced; neutrophils cease trafficking to sites of inflammation; macrophages clear the inflammatory milieu by phagocytosis of microbes and apoptotic neutrophils in a process termed efferocytosis (Savill et al., 1989, Schwab et al., 2007); and neutrophils at the mucosal interface are released by CD55 from the apical surface of epithelial cells for luminal clearance (Campbell et al., 2007). As tissue leukocytes recede from sites of acute inflammation, levels of proinflammatory cytokines and chemokines also decrease. At this turning point, metabolism of polyunsaturated fatty acids switches from conversion to pro-inflammatory mediators, such as leukotrienes and prostaglandins, to pro-resolving mediators, such as lipoxins (Levy et al., 2001). These pro-resolving mediators act as agonists at specific receptors to contribute to the restoration of host tissues to a homeostatic state (Serhan, 2014).

Excessive acute inflammation and chronic unresolved inflammation have been linked to important and morbid human lung diseases, including acute respiratory distress syndrome (ARDS), asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Current research is determining whether the ungoverned inflammation in these diseases reflects a failure of the healthy resolution program in the lungs. This review will examine research in animal models of disease in which SPMs have been shown to increase survival and promote resolution of inflammation as well as several human diseases that are associated with dysregulation of SPM pathways, including SPMs generated from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

Section snippets

Polyunsaturated fatty acids are available during acute inflammation

Polyunsaturated fatty acids (PUFAs) are known to be essential nutrients that are not produced by humans to any significant extent. The omega 6 PUFA arachidonic acid is incorporated into cellular phospholipids and on cellular activation is liberated by phospholipase A2 enzymes for enzymatic conversion to prostaglandins, leukotrienes, or lipoxins (Samuelsson et al., 1987, Serhan, 2007). Omega 3 fatty acids are found primarily in dietary fish oils (Burr and Burr, 1929, Calder, 2013). The omega 3

DHA and EPA are enzymatically transformed to SPMs

Essential PUFAs serve an important role in regulating the acute inflammatory response as substrates for enzymatic conversion to potent lipid-derived mediators (Samuelsson et al., 1987). During resolution of a self-limited experimental model of acute inflammation in vivo, liquid chromatography tandem mass spectrometry (LC–MS/MS)-based lipid mediator metabolomic profiling revealed that EPA and DHA are enzymatically converted into specific bioactive compounds that display protective

Cellular actions of SPMs

Acute inflammation is essential for host defense and survival. Controlling and resolving inflammation to protect vital tissues and organs from collateral damage and further injury is equally as important. The acute inflammatory response resolves in an active way that engages specific cellular events. Neutrophils begin to die via induction of cytokines and T cells undergo activation-induced programmed cell death. SPMs induce the expression of CCR5 on T cells, which scavenges residual

ALX/FPR2 receptor

The ALX/FRP2 receptor is present on human neutrophils, eosinophils, airway epithelium, monocytes, macrophages, T cells, synovial fibroblasts, and intestinal epithelial cells (Bonnans et al., 2006, Chiang et al., 2006, Fiore et al., 1994, Maddox et al., 1997) as well as human NK cells and ILCs (Barnig et al., 2013) (Fig. 4). Orthologs of the ALX receptor are expressed in mice (Takano et al., 1997) and rats (Chiang et al., 2003) with preserved structure and function. The ALX receptor is a

Human lung diseases are associated with decreased SPMs

In humans, the actions of the resolvins, protectins, and maresins in vivo are just beginning to be investigated. RvD1, RvD2, and RvE1 can be detected in samples of peripheral venous blood from healthy individuals and their levels are modified by omega-3 fatty acid dietary supplementation (Colas et al., 2014, Mas et al., 2012, Psychogios et al., 2011). A recent study has described the upregulation of RvD1 and RvD2 in the plasma of patients recently diagnosed with pulmonary tuberculosis (Frediani

Allergic asthma

In mouse models of allergic asthma/airway inflammation, SPMs display potent immunomodulatory actions (Table 3). In acute and chronic allergen-driven models, RvE1 promotes the resolution of inflammatory airway responses by inhibiting airway eosinophil and lymphocyte recruitment, suppressing the production of IL-6, IL-13, and IL-23, promoting LXA4 and IFN-γ production, and decreasing airway hyperresponsiveness to inhaled methacholine (Flesher et al., 2014, Haworth et al., 2008). When administered

Conclusions

In order to maintain health, the body must respond to a wide array of insults including injury, infection, and noxious stimuli. In particular, the lung is exposed to this milieu of agents potentially through each breath. The host needs to respond to respiratory pathogens and allergens as well as toxins and irritants by mounting an acute inflammatory response to resolve the insult in a timely manner and restore homeostasis. If there is a failure of catabasis to resolve the acute immune response,

Conflict of interest

B.D.L. is an inventor on patents assigned to Brigham and Women’s Hospital; some of these patents (those pertaining to Rvs) are licensed to Resolvyx Pharmaceuticals. The interests of B.D.L. were reviewed and are managed by the Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. M.G.D. has no conflict of interest to disclose.

Acknowledgments

This work was funded in part by US National Institutes of Health Grants R01-HL122531, U01-HL108712, U10-HL109172, U24-AI118656 and P01-GM095467.

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