New anti-inflammatory approaches in COPD

doi:10.1016/j.ddstr.2004.11.013

Drug Discovery Today: Therapeutic Strategies

Volume 1, Issue 3, December 2004, Pages 335-343

https://doi.org/10.1016/j.ddstr.2004.11.013 Get rights and content

Inflammation in chronic obstructive pulmonary disease (COPD) is characterised by increased numbers of neutrophils, macrophages and CD8⁺ T-lymphocytes, and the release of multiple inflammatory mediators (leukotrienes, chemokines, cytokines). It appears to be resistant to corticosteroids. This circumstance is stimulating a search for novel anti-inflammatory therapies that might prevent the relentless progression of the disease. For this reason, attention has largely been focused on inhibition of recruitment and activation of inflammatory cells, and on antagonism of their products.

Section Editors:

Roy Goldie – University of Western Australia, Western Australian Institute for Medical Research, Australia

Duncan Stewart – Terrence Donnelly Research Laboratories, Division of Cardiology, St Michael's Hospital and University of Toronto, Toronto, Ontario, Canada

Chronic obstructive pulmonary disease (COPD) is a degenerative inflammatory lung disease often associated with long-term cigarette smoking. Despite the inflammatory nature of COPD, currently available anti-inflammatory therapies such as those used in asthma and rheumatoid arthritis for example, are not clinically very effective in blunting either the symptoms or the progression of COPD. Accordingly, there is an urgent need to discover novel, effective anti-inflammatory treatments for this disease. Matera and Cazzola have been leading researchers in the COPD field for many years and have put together a very useful summary of the state-of-the-art development of clearly and potentially useful anti-inflammatory strategies in COPD.

Introduction

Chronic inflammation plays a central role in chronic obstructive pulmonary disease (COPD). It is characterised by an increase in neutrophils, macrophages and CD8⁺ T-lymphocytes in small and large airways as well as in lung parenchyma and pulmonary vasculature [1]. Alveolar macrophages play a crucial part in orchestrating this inflammation through the release of proteases such as matrix metalloproteinase (MMP) 9, inflammatory cytokines such as tumour necrosis factor (TNF)-α and chemokines such as interleukin (IL)-8 that attract neutrophils into the airways.

Corticosteroids are highly effective as an anti-inflammatory treatment in a wide range of chronic inflammatory diseases, but patients with COPD are poorly responsive to these drugs. This probably happens because cigarette smoking and oxidative stress impair histone deacetylase 2 function [2]. Nonetheless, in severe COPD patients, combinations of inhaled corticosteroids and long-acting β₂-agonists show an additive effect, suggesting an interaction between the two moieties that can have a positive effect [3].

Section snippets

Emerging anti-inflammatory strategies

Suppression of the inflammatory response is a logical approach to the treatment of COPD and might improve symptoms such as cough and mucus secretion, improve health status and reduce exacerbations. In the long-term, such treatments should reduce disease progression. However, hitherto, no therapeutic agent has been shown to reduce the numbers of the important inflammatory cells, macrophages, neutrophils and CD8⁺ lymphocytes in COPD [4]. For this reason, attention has largely been focused on

Conclusions

The recently published American Thoracic Society/European Respiratory Society guidelines [44] identify a pressing need to develop agents that suppress the inflammation associated with COPD and prevent disease progression. As illustrated in this review (which is not exhaustive because of the on-going identification of new targets that might allow the development of novel approaches by the pharmaceutical industry), there are some interesting therapeutic attempts, which are under pharmacological

Glossary

CXC: chemokine ligand.
GAG: glycosaminoglycan.
ICAM: intercellular adhesion molecule that mediates attachment, spreading and migration of polymorphonuclear leukocytes.
IL: interleukin; mediator of inflammatory and immune reactions.
LFA: lymphocyte function antigen, an adhesion molecule that appears to play a major role in T-lymphocyte adhesion to vascular endothelium, cytotoxic function, and activation.
LTB₄: leukotriene B₄, an extremely potent lipid inflammatory mediator, derived from membrane phospholipids by

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Cited by (9)

Treating systemic effects of COPD
2007, Trends in Pharmacological Sciences
The emerging recognition that chronic obstructive pulmonary disease (COPD) is a complex disorder, characterized not only by local pulmonary inflammation, but also by systemic inflammation that might have an adverse impact on various extrapulmonary organs, such as the blood vessels and the heart, among others, emphasizes the need for new and more effective forms of therapy for this debilitating disorder. Fortunately, many of the ‘standard’ therapeutic options used to treat COPD have the potential to influence systemic inflammation. Moreover, several new therapeutic strategies aimed at controlling the underlying inflammatory processes of COPD more specifically are under development. Unfortunately, we still do not know whether treatment of lung inflammation decreases, for example, the risk of acute cardiac events, progression of atherosclerosis or thrombotic events. It is also unclear whether, alternatively, treatment of heart disease can affect the progression of lung disease. Nonetheless, initial data seem to indicate that drugs, such as statins, ACE inhibitors, AT1 receptor blockers and PPAR agonists, used to treat a co-morbid condition have the potential to benefit COPD patients.
The effective treatment of COPD: Anticholinergics and what else?
2006, Drug Discovery Today: Therapeutic Strategies
Long-acting bronchodilator therapy should be considered when a COPD patient is symptomatic. For patients whose conditions are not sufficiently controlled by monotherapy, combining medications of different classes seems a convenient treatment for obtaining better results. The current opinion is that it is advantageous to develop inhalers containing several classes of long-acting bronchodilator drugs in an attempt to simplify treatment regimes as much as possible and to serve as a basis for improved ‘triple therapy’ combinations through co-formulation with novel anti-inflammatory compounds, such as inhaled PDE4 inhibitors, that could deliver three complementary therapeutic effects.
Treatments for COPD
2005, Respiratory Medicine
The multicomponent nature of chronic obstructive pulmonary disease (COPD) has provided a challenging environment in which to develop successful treatments. A combination of pharmacological and non-pharmacological approaches is used to combat this problem, and an overview of these approaches and their possible future direction is given.
Bronchodilators are the mainstay of COPD treatment and can be combined with inhaled corticosteroids for greater efficacy and fewer side effects. A new generation of pharmacotherapeutic agents, most notably phosphodiesterase-4 inhibitors, which are already in the advanced stages of clinical development, and leukotriene B₄ inhibitors (in early clinical development), may shape future treatment as further insight is gained into the pathological mechanisms underlying COPD.
Non-pharmacologic treatments for COPD include long-term oxygen therapy (LTOT), nasal positive pressure ventilation (nPPV), pulmonary rehabilitation and lung-volume-reduction surgery (LVRS). Apart from smoking cessation, LTOT is the only treatment to date which has been shown to modify survival rates in severe cases; thus its role in COPD is well defined. The roles of nPPV and LVRS are less clear, though recent progress is reported here.
In the future, it will be important to establish the precise value of the different treatments available for COPD—evaluating both clinical and physiological endpoints and using the data to more accurately define candidate patients accordingly. The challenge will be to develop this base of knowledge in order to shape future research and allow clinicians to deliver tailored COPD management programmes for the growing number of patients afflicted with this disease.
New treatments for COPD in the elderly
2014, Current Pharmaceutical Design
Emerging anti-inflammatory strategies for COPD
2012, European Respiratory Journal
Emerging drugs for chronic obstructive pulmonary disease
2012, Expert Opinion on Emerging Drugs

View all citing articles on Scopus

View full text

Respiratory diseasesNew anti-inflammatory approaches in COPD

Section Editors:

Introduction

Section snippets

Emerging anti-inflammatory strategies

Conclusions

Glossary

Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis

Thorax

Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase

Lancet

Inhaled combination therapy with long-acting ß2-agonists and corticosteroids in stable COPD

Chest

COPD: is there light at the end of the tunnel?

Curr. Opin. Pharmacol.

Characterisation of adhesion receptors mediating lymphocyte adhesion to bronchial endothelium provides evidence for a distinct lung homing pathway

Thorax

Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease

Am. J. Respir. Crit. Care Med.

Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses

Clin. Exp. Allergy

Efaluzimab in the treatment of psoriasis

Ann. Univ. Mariae Curie Sklodowska [Med.]

Adenosine A2A receptor agonists as anti-inflammatory agents

Curr. Opin. Investig. Drugs

Therapy for chronic obstructive pulmonary disease in the 21st century

Drugs

Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease

Drugs

Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study

Lancet

Anti-inflammatory effects of the phosphodiesterase 4 inhibitor cilomilast (Ariflo) in COPD

Am. J. Respir. Crit. Care Med.

Efficacy of once-daily roflumilast, a new, orally active, selective phosphodiesterase 4 inhibitor, in chromic obstructive pulmonary disease

Am. J. Respir. Crit. Care Med.

Phosphodiesterase 4 inhibitors for the treatment of COPD

Chest

Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey

Brain Res.

Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-α responses

Proc. Natl. Acad. Sci. USA

In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyo xylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration

J. Pharmacol. Exp. Ther.

Interleukin-10 level in sputum is reduced in bronchial asthma COPD and in smokers

Eur. Respir. J.

IL-10 and its related cytokines for treatment of inflammatory bowel disease

World J. Gastroenterol.

Cytokines and therapy in COPD: a promising combination?

Chest

The effect of infliximab in patients with chronic obstructive pulmonary disease

Chest

Respiratory diseases
New anti-inflammatory approaches in COPD

Inhaled combination therapy with long-acting ß₂-agonists and corticosteroids in stable COPD