Associate editor: P. Foster
Treating neutrophilic inflammation in COPD by targeting ALX/FPR2 resolution pathways

https://doi.org/10.1016/j.pharmthera.2013.07.007Get rights and content

Abstract

Neutrophilic inflammation persists in COPD despite best current therapies and it is particularly resistant to inhaled glucocorticosteroids. Persistent neutrophil activation not only contributes to matrix breakdown, but can maintain inflammation through the release of endogenous damage associated molecule patterns (DAMPs). Inhibiting excessive neutrophilic inflammation is challenging as many pathogen recognition receptors can initiate migration and the targeting of downstream signaling molecules may compromise essential host defense mechanisms. Here, we discuss new strategies to combat this inflammation in COPD by focusing on the anti-inflammatory role of ALX/FPR2 receptors. ALX/FPR2 is a promiscuous G-protein coupled receptor (GPCR) responding to lipid and peptide agonists that can either switch on acute inflammation or promote resolution of inflammation. We highlight this receptor as an emerging target in the pathogenesis of COPD because known ALX/FPR2 endogenous agonists are enriched in COPD. Serum Amyloid A (SAA) has recently been discovered to be abundantly expressed in COPD and is a potent ALX/FPR2 agonist that unlike almost all other inflammatory chemoattractants, is induced by glucocorticosteroids. SAA not only initiates lung inflammation via ALX/FPR2 but can allosterically modify this receptor so that it no longer transduces pro-resolving signals from endogenous lipoxins that would otherwise promote tissue healing. We propose that there is an imbalance in endogenous and microbial ALX/FPR2 receptor agonists in the inflamed COPD lung environment that oppose protective anti-inflammatory and pro-resolution pathways. These insights open the possibility of targeting ALX/FPR2 receptors using synthetic agonists to resolve persistent neutrophilic inflammation without compromising essential host defense mechanisms.

Introduction

Chronic obstructive pulmonary disease (COPD) is estimated to affect 5% of the global adult population and is predicted to become the third leading cause of death by 2030 (Jemal et al., 2005). This is primarily as a consequence of long term tobacco smoking in an increasingly aging population (Mannino & Buist, 2007), however exposure to indoor biomass fuels is also related to higher rates of COPD among women in developing countries (Lopez et al., 2006). COPD is characterized by chronic airway inflammation involving both innate and adaptive cells that accumulate with disease progression ( Saetta et al., 1999, Hogg, 2004, Hogg et al., 2004), which is very persistent as smoking cessation fails to fully resolve this inflammatory profile (Willemse et al., 2005). The accumulation of inflammatory cells contributes to key pathological processes in COPD including small airway narrowing, destruction of alveolar walls (emphysema) and mucous hypersecretion (reviewed in Barnes, 2008).

The establishment of chronic inflammation in COPD is multi-factorial; however the presence of pathogenic microbes in the airways is likely to be a major cause. It is estimated that about 50% of COPD patients are chronically colonized with potentially pathogenic microorganisms including Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis (Monso et al., 1995, Pela et al., 1998). The presence of microbial pathogens in the lower airways is related to defective innate and cellular immunity as a consequence of chronic cigarette smoke exposure (reviewed in Stampfli & Anderson, 2009). There is a direct relationship between colonization and the degree of airway inflammation. Colonized COPD patients display worse health status and increased neutrophilic inflammation, as reflected in increased levels of interleukin-8 (CXCL8), leukotriene B4 (LTB4), and neutrophil elastase (Banerjee et al., 2004). Colonization is also associated with increased airway shedding of microbial products such as endotoxin (Sethi et al., 2006) that may perpetuate ongoing inflammation, neutrophil activation and subsequent tissue damage through persistent activation of pathogen recognition receptors (PRRs).

In addition, neutrophilic inflammation is particularly elevated during acute exacerbations of COPD (AECOPD) that are mainly triggered by acquisition of a new respiratory pathogen (Papi et al., 2006). AECOPD are responsible for an increased risk of mortality, particularly when patients experience recurrent severe exacerbations that require hospitalization (Soler-Cataluna et al., 2005). They result in a more rapid decline in lung function (Donaldson et al., 2002), impaired health related quality of life (Donaldson et al., 2005) and have a major impact on health care expenditure (Sullivan et al., 2000). Viral infections are common, accounting for approximately 50% of AECOPD and a causal relationship has been recently described (Hutchinson et al., 2007, Mallia et al., 2011). Bacterial infections are also a common cause of purulent AECOPDs that are associated with a marked increase in neutrophilic inflammation (Gompertz et al., 2001), where clinical severity tracks with the degree of airway and systemic inflammation (Sethi et al., 2008).

Section snippets

Role of colonization and acute exacerbations of chronic obstructive pulmonary disease

Limited exocytosis of proteinases in primary azurophilic granules is normally required for efficient intracellular killing of microorganisms in the phagolysosome (Belaaouaj et al., 1998). The majority of neutrophil elastase is expressed on the activated neutrophil surface as a mechanism to facilitate egress from the vasculature and limit damage to surrounding tissue (Owen et al., 1995). Anti-proteinases such as α1-antitrypsin (α1-AT), secretory leukoprotease inhibitor (SLPI) and tissue

Prominent signaling pathways activated in chronic obstructive pulmonary disease

Due to their pathogen sensing capacity, PRRs regulate inflammation in response to chronic airway colonization and AECOPD. The recognition of bacterial and viral products by PRRs expressed on resident and recruited cells will modulate the degree of neutrophilic inflammation. The Toll-Like Receptor (TLR) family including TLR2 and TLR4 are capable of initiating neutrophilic inflammation in response to cigarette smoke by sensing oxidants (Paul-Clark et al., 2009) independently of classic

Current therapies

Neutrophilic inflammation in COPD remains a challenging area of unmet medical need as the targeting of excessive inflammation must be achieved without compromising essential host defense mechanisms required for the clearance of infection. Antibiotics are used in AECOPDs as treatment success rates are higher in patients with features of an infectious exacerbation (Anthonisen et al., 1987). Long-term azithromycin therapy in COPD has also been shown to reduce exacerbation frequency (Albert et al.,

Role of Serum Amyloid A and ALX/FPR2 in neutrophilic inflammation

ALX/FPR2 displays diverse ligand affinities, with over 30 peptides described to date and is unique in that it is the only FPR member to bind to the eicosanoid LipoxinA4 (LXA4) (Ye et al., 2009). As ALX/FPR2 ligands can promote opposing biological actions, their relative abundance may contribute to the intensity and resolution of airway inflammation in COPD. Specifically, this receptor complex is known to play a central role in resolution processes that are required for the termination of acute

Serum Amyloid A blocks resolution of inflammation mediated by ALX/FPR2

The temporal progression of acute inflammatory responses is normally counterbalanced by a secondary phase that includes i) induction of anti-inflammatory mediators that stop neutrophil infiltration and ii) active resolution processes that promote clearance of tissue inflammation and invading microbes with restoration of tissue integrity and function. Eicosanoids, such as lipoxins, and new families of endogenous mediators, termed resolvins and protectins are integral to the control of local

Concluding remarks

In summary, we have provided a comprehensive overview of the mechanisms that can cause persistent neutrophilic inflammation in COPD and AECOPD and the consequences of unregulated neutrophil activation in the airways. We have also provided a summary of the current and emerging therapies aimed at controlling excessive neutrophilic inflammation in this debilitating disease. Since there is a diverse suite of microbial and endogenous ligands that act on many PRRs to initiate airway inflammation, a

Conflict of interest statement

Dr. Levy is a co-inventor on patents on lipoxins in airway disease that are assigned to Brigham and Women's Hospital and licensed for clinical development. The remaining authors have no competing interests to disclose.

Acknowledgments

This work is supported in part by the National Health Medical Research Council (NHMRC) of Australia and the US National Institutes of Health grants HL068669, HL107166, HL109172 and GM095467.

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