Novel drug targets for asthma and COPD: Lessons learned from in vitro and in vivo models

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Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent respiratory diseases characterized by airway inflammation, airway obstruction and airway hyperresponsiveness. Whilst current therapies, such as β-agonists and glucocorticoids, may be effective at reducing symptoms, they do not reduce disease progression. Thus, there is a need to identify new therapeutic targets. In this review, we summarize the potential of novel targets or tools, including anti-inflammatories, phosphodiesterase inhibitors, kinase inhibitors, transient receptor potential channels, vitamin D and protease inhibitors, for the treatment of asthma and COPD.

Introduction

Obstructive airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), represent a major health problem worldwide. According to the World Health Organization (WHO), asthma is the most common chronic disease among children [1], and it is predicted that COPD will become the third leading cause of death worldwide by 2030 [2], [3].

The common pathophysiological components of asthma and COPD are airway inflammation, airway obstruction and airway hyperresponsiveness (AHR); the differences are mainly related to the cellular and molecular features of inflammation and the reversibility of airflow obstruction. Airway inflammation in allergic asthma is usually eosinophilic, whereas COPD is associated with predominantly neutrophilic inflammation. However, some non-allergic endotypes of asthma, such as exercise-induced, aspirin-sensitive and infection-induced asthma, may present with little to no eosinophilic inflammation. Severe, steroid-resistant and obesity related asthma endotypes are frequently associated with a neutrophilic inflammatory profile [reviewed in Ref. [4]]. Physiologically, asthma is typically characterized by reversible AHR, whereas COPD is characterized by airflow limitation that is not fully reversible and is usually progressive.

Whilst current asthma therapies, namely β-agonists and glucocorticoids, reduce airway inflammation, reverse bronchoconstriction and improve quality of life in the majority of patients, these treatments have little or no effect on the structural alterations associated with the disease. Furthermore, there remains a considerable population of people for whom these treatments are ineffective and thus their asthma is poorly controlled. Similarly, current treatments for COPD have limited efficacy in terms of inhibiting chronic inflammation and do not reverse the disease process or prevent its progression. Hence, there is a clear need to increase our understanding of disease processes, identify novel targets and develop new therapies. In this review, we provide an update on existing treatments and highlight novel emerging targets and treatments for asthma and COPD.

Section snippets

Novel anti-inflammatory drugs for the treatment of allergic asthma

Anti-inflammatory therapies for allergic asthma were introduced in the mid-20th century, and inhaled corticosteroids have been the primary therapy for asthma for the past 35 years [5]. In recent decades, research has focused on more specific targeting of the asthmatic inflammatory response, with the advent of anti-leukotriene and anti-IgE drugs. Ongoing studies in this area have provided promising results with regard to additional anti-inflammatory interventions.

Novel anti-inflammatory drugs for the treatment of COPD

Inflammation in COPD is characteristically distinct from other lung diseases and is less responsive to inhaled glucocorticoids compared to asthma. In acute exacerbations of COPD (AECOPD), which can be triggered by bacterial or viral infections, lung inflammation is dramatically increased [28]. It is crucial to understand the underlying contributions of different cell types, for example increased neutrophils and macrophages, and how these contribute to complicated cytokine and chemokine profiles

G-protein-coupled receptors (GPCRs) in asthma and COPD

Currently, β2-adrenoreceptor agonists and muscarinic receptor antagonists are the two main types of bronchodilators that provide effective symptomatic relief for the treatment of airway constriction [44]. These receptors are members of the G-protein coupled receptor (GPCR) family. GPCRs are a large family of cell surface receptors, characterized by the presence of seven membrane-spanning peptide chains. Agonist binding induces a conformational change and subsequently dissociation of the α

Phosphodiesterase inhibitors

Phosphodiesterases are a superfamily of enzymes involved in the regulation of cellular functions. Theophylline, a non-specific PDE inhibitor, has been used in the treatment of asthma and COPD for over 75 years as it promotes bronchodilation and inhibits inflammation. Despite its high oral bioavailability and anti-inflammatory, anti-proliferative and bronchodilator effects, its use has been hampered by its adverse effects. However, recent advancements in our understanding of PDE isoenzymes have

Targeting TRP channels

The transient receptor potential (TRP) family of ion channels are cation-selective transmembrane proteins which show a preference for Ca2+ ions [99], [100]. The TRP family of proteins consists of 28 members in six subfamilies (TRPC, TRPV, TRPM, TRPA, TRPP and TRPML) based on sequence homology [101]. They are known as cellular sensors as they respond to changes in the local environment [101]. Whilst expression of TRP channels has been mainly demonstrated in sensory nerve cells, they have also

Kinases

Kinases are key regulators of normal cellular functions, through the site-specific phosphorylation of a downstream substrate. As kinases are involved in diverse regulations of various cellular functions, they have become an obvious target for rational drug design for diseases such as asthma and COPD. In this section, we will briefly discuss the roles of various kinases that have been linked to the pathogenesis of asthma and COPD, including mitogen activated protein kinase (MAPK; e.g. extra

Vitamin D

Whilst vitamin D and its receptors are known for their role in bone mineralization and calcium homeostasis, there is growing evidence that vitamin D deficiency may contribute to respiratory diseases. Here, we discuss the role of vitamin D in asthma and COPD.

Matrix metalloproteinases (MMPs) as targets in asthma and COPD

MMPs are a family of zinc endopeptidases capable of degrading most components of the extracellular matrix. They exist in balance with their endogenous inhibitors, tissue inhibitors of MMPs (TIMPs). A disruption of this balance is a key event in the development of pulmonary diseases such as asthma and COPD where elevated levels of MMPs have been reported. Thus, targeting the MMPs may be an alternative therapeutic strategy.

New developments for combination therapy

The bronchodilating effectiveness of β2-adrenoreceptor agonists is influenced by functional antagonism by bronchoconstricting agents. Thus, studies in human [267], [268] and animal [269], [270] ASM preparations have demonstrated that the potency and efficacy of β2-adrenoreceptor agonists are gradually reduced in the presence of increasing concentrations of contractile stimuli, including muscarinic receptor antagonists and histamine. This reduced β2-adrenergic responsiveness may be due to

Future directions

In this review, we have highlighted some of the potential targets that are emerging for the treatment of asthma and COPD. However, due to space limitations, other potential candidates for future treatments such as Toll-like receptors, bitter taste receptors and the receptor for advanced glycation end products (RAGE) should also be considered (reviewed in Refs. [294], [295], [296], [297]).

Whilst significant advances in our understanding of the cellular and molecular mechanisms involved in the

Acknowledgements

K.E.B. is supported by the Medical Research Council (MRC), UK. S.J.B. is supported by the National Heart & Lung Institute, UK. C.D. is supported by an Australian Postgraduate Award. R.E.F has received funding from the Australian Postgraduate Award and Stan and Jean Perron PhD Top-Up Scholarship. Y.S. is supported by the Wellcome Trust. J.R.J. is supported by an Imperial College London Junior Research Fellowship and an MRC New Investigator Award. L.M.M. was supported by the National Health and

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