Associate editor: P. Foster
Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis

https://doi.org/10.1016/j.pharmthera.2009.06.004Get rights and content

Abstract

Obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major global health issues. Although considered as distinct diseases, airway inflammation is a key underlying pathophysiological process in asthma, COPD and bronchiectasis. Persistent neutrophilic airway inflammation (neutrophilic bronchitis) occurs with innate immune activation and is a feature of each of these airway diseases. Little is known about the mechanisms leading to neutrophilic bronchitis and few treatments are effective in reducing neutrophil accumulation in the airways.

There is a similar pattern of inflammatory mediator release and toll like receptor 2 expression in asthma, COPD and bronchiectasis. We propose the existence of an active amplification mechanism, an effector arm of the innate immune system, involving toll like receptor 2, operating in persistent neutrophilic bronchitis.

Neutrophil persistence in the airways can occur through a number of mechanisms such as impaired apoptosis, efferocytosis and mucus hypersecretion, all of which are impaired in airways disease. Impairment of neutrophil clearance results in a reduced ability to respond to bacterial infection. Persistent activation of airway neutrophils may result in the persistent activation of the innate immune system resulting in further airway insult.

Current therapies are limited for the treatment of neutrophilic bronchitis; possible treatments being investigated include theophylline, statins, antagonists of pro-inflammatory cytokines and macrolide antibiotics. Macrolides have shown great promise in their ability to reduce airway inflammation, and can reduce airway neutrophils, levels of CXCL8 and neutrophil proteases in the airways. Studies also show improvements in quality of life and exacerbation rates in airways diseases.

Introduction

Obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major global health issues. Airway inflammation is a key element of both diseases and assessment of the pattern of granulocyte infiltration is a useful indicator of likely mechanisms as well as treatment responsiveness. Persistent neutrophilic airway inflammation (neutrophilic bronchitis; Fig. 1) occurs with innate immune activation and is considered a typical feature of COPD. However, a prominent neutrophilic bronchitis is not restricted to COPD, and is also a significant feature of other obstructive airway diseases such as bronchiectasis, (Simpson et al., 2007) allergic bronchopulmonary aspergillosis (ABPA), (Wark et al., 2000) and the neutrophilic asthma sub-type. (Simpson et al., 2006) The mechanisms which underpin the development of airway neutrophilia appear to be similar and remarkably consistent across these different obstructive airway diseases. The induction of neutrophilic bronchitis involves upregulated gene expression and protein secretion of the potent neutrophil chemoattractant CXCL8 (Fig. 2) (Simpson et al., 2007), as well as release of neutrophil proteases. This commonality of features suggests similar mechanisms may be operating to potentiate neutrophilic bronchitis in the various obstructive airway diseases, and also that similar therapeutic approaches may be beneficial in this diverse range of airway diseases. This review will examine these issues and the mechanisms and potential therapy of neutrophilic bronchitis across different obstructive airway diseases.

Section snippets

Burden of illness from obstructive airways diseases

The diseases that are associated with airflow obstruction include asthma, COPD, bronchiectasis as well as less common conditions such as diffuse panbronchiolitis, bronchiolitis associated with connective tissue diseases, and obliterative bronchiolitis associated with transplantation (Table 1). Interestingly, a neutrophilic bronchitis (Fig. 1) can characterise most of these diseases. Asthma and COPD are the most common obstructive airway diseases with each affecting approximately 10% of the

Neutrophilic bronchitis in obstructive airways disease

Airway inflammation is recognised as a key underlying pathophysiological process in asthma, COPD and bronchiectasis. The inflammatory response in asthma is heterogeneous, with noneosinophilic forms of the disease increasingly recognised. Noneosinophilic asthma can exhibit a neutrophilic pattern, or a pattern with normal levels of airway granulocytes, termed paucigranulocytic asthma.(Simpson et al., 2006) Characterisation of inflammatory subtypes of asthma is useful in determining treatment and

Mechanisms linking neutrophilic bronchitis across obstructive airways diseases

Patients with neutrophilic asthma, COPD, bronchiectasis and ABPA are all characterized by an increased number of airway inflammatory cells (increased total cell count) and an increased proportion of neutrophils in sputum. One of the key mediators involved in neutrophil influx into the lung is the chemokine CXCL8. When compared to healthy people, there are increased levels of CXCL8 in each of these conditions, with increases in both CXCL8 protein and gene expression for CXCL8 (Wark et al., 2000,

Neutrophil Activation Cycle

We propose the existence of an active amplification mechanism operating in persistent neutrophilic bronchitis across different airway diseases. This involves positive feedback interactions between CXCL8, neutrophils, and the released neutrophil proteases, NE and MMP-9 (Fig. 3).

The biological mechanisms responsible for this positive feedback cycle in neutrophilic bronchitis have been well characterised using in vitro systems. When cultured neutrophils are treated with CXCL8, MMP-9 is rapidly

Mechanisms of neutrophil persistence

Removal of neutrophils from the airways involves pre-programmed apoptosis and is generally followed by phagocytosis of apoptotic cells by macrophages (termed efferocytosis) resulting in the resolution of neutrophilic inflammation. Impairment in either of these processes may lead to secondary necrosis of neutrophils and release of proteolytic enzymes (NE and MMP-9) as well as neutrophil chemoattractants (CXCL8). Perpetuation of the Neutrophil Activation Cycle through either impaired apoptosis or

The innate immune response and neutrophilic bronchitis

The Neutrophil Activation Cycle that typifies persistent neutrophilic bronchitis (Fig. 3) represents an effector arm of the innate immune response. In OAD, the effectors responsible for triggering this cycle remain unknown. It is known however; that toll like receptor (TLR)s have a well established ‘sensing’ and signalling role in the initiation of innate immune responses. TLRs are germ-line encoded receptors that recognise specific pathogen associated molecular patterns. Pathogen associated

The role of TLR2 in the Neutrophil Activation Cycle

TLR2 expression can be upregulated by a variety of stimuli including bacterial products (such as LPS, heat shock proteins, lipoteichoic acid and peptidoglycan), pro-inflammatory cytokines and corticosteroids. (Shuto et al., 2002, Hayashi et al., 2003, Hermoso et al., 2004, Sakai et al., 2004) Corticosteroids are the mainstay treatment of asthma and are used widely in COPD. The influence of corticosteroids on the upregulation of the innate immune response, in particular of TLR2 activation,

Macrolides

The anti-inflammatory effects of macrolide antibiotics are well-established. Macrolide antibiotics such as azithromycin have separate and distinct antibiotic and anti-inflammatory actions. As antibacterial agents, macrolides have been widely used in the treatment of infections caused by atypical bacteria such as Chlamydia pneumoniae and Mycoplasma pneumoniae which are associated with OAD. Macrolide antibiotics have become first line therapy in diffuse panbronchiolitis and many reports are now

Future directions

This review indicates several future research directions. The role of TLR2 in airways disease requires further elucidation, primarily in studies of different groups of patients with airways disease, and before and after disease exacerbation. There are opportunities to test the clinical efficacy of some of the treatments highlighted here, as well as to identify treatments that improve neutrophil removal, reduce neutrophil necrosis and reduce innate immune response. A critical question is to

Conclusions

Persistent neutrophilic bronchitis is a common feature of a variety of obstructive airways diseases. The presence of persistent neutrophilic inflammation results in excessive release of damaging neutrophil proteases NE and MMP-9 as well as the chemoattractant CXCL8. Little is understood about the inflammatory processes which lead to the persistence and activation of neutrophils in the airways but impairment of efferocytosis and mucus hypersecretion may be involved, processes which are further

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