Emerging airway smooth muscle targets to treat asthma

doi:10.1016/j.pupt.2012.08.008

Pulmonary Pharmacology & Therapeutics

Volume 26, Issue 1, February 2013, Pages 132-144

https://doi.org/10.1016/j.pupt.2012.08.008 Get rights and content

Abstract

Asthma is characterized in part by variable airflow obstruction and non-specific hyperresponsiveness to a variety of bronchoconstrictors, both of which are mediated by the airway smooth muscle (ASM). The ASM is also involved in the airway inflammation and airway wall remodeling observed in asthma. For all these reasons, the ASM provides an important target for the treatment of asthma. Several classes of drugs were developed decades ago which targeted the ASM – including β-agonists, anti-cholinergics, anti-histamines and anti-leukotrienes – but no substantially new class of drug has appeared recently. In this review, we summarize the on-going work of several laboratories aimed at producing novel targets and/or tools for the treatment of asthma. These range from receptors and ion channels on the ASM plasmalemma, to intracellular effectors (particularly those related to cyclic nucleotide signaling, calcium-homeostasis and phosphorylation cascades), to anti-IgE therapy and outright destruction of the ASM itself.

Introduction

Asthma is a common respiratory disease that affects approximately 235 million people worldwide (WHO, Fact Sheet No 307 May 2011). It is characterized by airflow obstruction, airway inflammation and airway remodeling. Classically, the airway smooth muscle (ASM) cell was believed to contribute to the pathogenesis of asthma through its contractile properties: airway hyperresponsiveness (AHR), one of the main characteristics in asthma, refers to excessive narrowing of ASM induced by stimuli which in otherwise normal individuals cause only limited airway narrowing. However it is now widely accepted that ASM also functions as an immunomodulatory cell and contributes to the airway inflammation and structural alterations associated with the disease. Thus, an increase in ASM bulk not only exacerbates airway contraction resulting in increased airway narrowing but it may also be a major driving force of disease progression. Since the ASM plays such a central role it is reasonable to assume that targeting it may be beneficial for the treatment of asthma.

Although current asthma therapies, namely glucocorticoids and β2-adrenoceptor (β2AR) agonists, which abrogate airway inflammation, reverse bronchoconstriction and improve quality of life, are effective in controlling disease symptoms in the majority of patients, a considerable population of patients with poorly controlled asthma remains. Furthermore, these life-long therapies only treat the symptoms and they have little or no effect on the structural alterations associated with asthma. Taken together, these points highlight the need for the development of new or improved therapies. It is only with a greater understanding of the cellular and molecular mechanisms that regulate ASM function that we can begin to develop new treatment strategies for asthma.

In this review, we provide an update on existing ASM targets and highlight new and emerging concepts for the treatment of asthma. Space limitations do not allow us to be all inclusive or comprehensive on this subject; instead, we focus particularly on the new directions being pursued by the attendees of the meeting. We begin with stimulation of the ASM by its plasmalemmal receptors for external stimuli – the G protein-coupled receptors, or GPCRs – and several pharmacological concepts related to their function (desensitization; constitutive activity; biased agonism). In addition, we briefly summarize one novel class of GPCR – the bitter taste receptor – given the considerable attention which this family has recently received in the airway field. Next, we consider several diverse signaling events triggered by those GPCRs, including the cyclic nucleotide/phosphodiesterase cascade, elevation of cytosolic calcium concentration via 4 different Ca²⁺-influx pathways, and activation of various kinases. Finally, we move away from these strategies of treating asthma through control of an excited ASM, by instead now either controlling airway inflammation (anti-IgE therapy), or by removing the ASM entirely (bronchial thermoplasty).

Section snippets

G protein-coupled receptors

G protein-coupled receptors (GPCR) on human ASM cells have been a major target for asthma therapy for decades and GPCR ligands still constitute the frontline treatment of asthma today. This widespread clinical use of GPCR ligands is a result of the expanded body of knowledge regarding GPCR identity, localization, downstream signaling pathways, ligand specificity and duration as well as improved methods of administration.

In addition to finding new GPCR targets, the current challenge is to

Phosphodiesterases and cAMP

Phosphodiesterase (PDE) inhibitors have gained widespread interest for their potential to treat a variety of diseases including asthma and chronic obstructive pulmonary disease (COPD). Physiological and pharmacological studies have highlighted the important role of PDEs in the control of airway function, inflammation and remodeling. Theophylline, a non-specific PDE inhibitor, has been used in the treatment of asthma since the 1930s, as pharmacological inhibition of PDEs augments the second

Calcium

Calcium plays a key role in the initiation and maintenance of ASM contraction and is closely coupled to AHR [48], [49], given that it activates myosin light chain kinase in particular, as well as other kinases which participate in excitation-contraction coupling, such as RhoA kinase [50]. [Ca²⁺]_i can be increased due to Ca²⁺-influx through Ca²⁺ channels in the plasma membrane (PM)—such as voltage-dependent Ca²⁺ channels (VDCC), and store-operated Ca²⁺ channels (SOCC)—and Ca²⁺-release through Ca

Kinases

Phosphatidylinositol 3-kinase, Rho kinase and tyrosine kinases as novel therapeutic targets.

ASM function is also regulated through the complex interaction between receptor signaling and the downstream kinases, phosphatidylinositol 3-kinase (PI3K), Rho kinase and tyrosine kinases. Our understanding of the role(s) of these kinases in ASM function is increasing with the availability of new and more targeted inhibitors. Fig. 4 summarizes the role(s) of PI3-kinase, Rho kinase and tyrosine kinases as

Anti-IgE therapy

Owing to a central role of IgE in allergic asthma, a recombinant, humanized monoclonal anti-IgE antibody, omalizumab has been approved for the treatment of allergic asthma [129], [130]. Omalizumab blocks the binding of IgE with its Fc receptors [131], and acts by reducing serum IgE levels, FcεRI expression on inflammatory cells, and by attenuating tissue mast cell function [130], [132]. Although some studies were unable to detect FcεRI expression in ASM cells [133], [134], [135], others suggest

Bronchial thermoplasty

Rather than trying to control pharmacologically the mechanical output of the smooth muscle using inhibitors of excitatory responses (anti-cholinergics; anti-histamines; anti-leukotrienes) or agonists which promote relaxant responses (β-agonists; PDE inhibitors), some have hypothesized that it might be possible to remove the ASM entirely. Others have questioned the physiological importance or even usefulness of the ASM [149] – in fact, referring to it as the appendix of the lung – and gone on to

Future directions

Although there is some debate as to whether ASM plays an important role at all in normal airway physiology [149], very few would contest that ASM is a major problem in asthma. Whether that problem is due to altered function of the individual ASM cells and/or hyperplasia of the whole airway wall tissue, bronchodilation is the singular goal of rescue asthma therapy. Despite these facts, there have been no substantially new pharmacological agents introduced to the market to target the ASM. For the

Funding sources

N.S.R. was supported by graduate studentship from the Canada Lung Association-Canadian Thoracic Society. S.S. was a recipient of the Alexander McFee Studentship, Faculty of Medicine, McGill University, Montréal, QC, Canada. O.O.O. is supported by the CIHR/IMPACT Strategic Training Fellowship. L.M.M was supported by the National Health and Medical Research Council, Australia and the LAM Australasia Research Alliance.

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¹: Sana Siddiqui is now at the Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.

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Emerging airway smooth muscle targets to treat asthma

Abstract

Introduction

Section snippets

G protein-coupled receptors

Phosphodiesterases and cAMP

Calcium

Kinases

Anti-IgE therapy

Bronchial thermoplasty

Future directions

Funding sources

Cell Signal

J Allergy Clin Immunol

Curr Opin Pharmacol

Pulm Pharmacol Ther

Eur J Pharmacol

Biochem Biophys Res Commun

Am J Hum Genet

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

J Biol Chem

Pulm Pharmacol Ther

J Am Coll Cardiol

Mol Ther

Int Immunopharmacol

J Biol Chem

Eur J Pharmacol

Signaling and regulation of G protein-coupled receptors in airway smooth muscle

Respir Res

Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle

FASEB J

Endogenous Gs-coupled receptors in smooth muscle exhibit differential susceptibility to GRK2/3-mediated desensitization

Biochemistry

Formoterol and salmeterol induce a similar degree of beta2-adrenoceptor tolerance in human small airways but via different mechanisms

Br J Pharmacol

Safe use of long-acting beta-agonists: what have we learnt?

Expert Opin Drug Saf

Agonizing over agonism: should asthmatics turn their beta-receptors on or off?

Proc Natl Acad Sci U S A

Beta2-adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Proc Natl Acad Sci U S A

Complementary anti-inflammatory effects of a beta-blocker and a corticosteroid in an asthma model

Naunyn Schmiedebergs Arch Pharmacol

Effects of acute and chronic administration of beta-adrenoceptor ligands on airway function in a murine model of asthma

Proc Natl Acad Sci U S A

Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model

Am J Respir Cell Mol Biol

New perspectives regarding beta(2) -adrenoceptor ligands in the treatment of asthma

Br J Pharmacol

Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD

Eur Respir J

Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction

Nat Med

Membrane potential-dependent and-independent tension in the canine tracheal muscle

J Pharmacol Exp Ther

Coupling mechanisms in airway smooth muscle

Am J Physiol

Ionic mechanisms and Ca(2+) regulation in airway smooth muscle contraction: do the data contradict dogma?

Am J Physiol Lung Cell Mol Physiol

Agonist-promoted homologous desensitization of human airway smooth muscle bitter taste receptors

Am J Respir Cell Mol Biol

Effect of bitter tastants on human bronchi

Nat Med

Regulation of TNF-alpha-induced eotaxin release from cultured human airway smooth muscle cells by beta2-agonists and corticosteroids

FASEB J

Identification, characterization and functional role of phosphodiesterase isozymes in human airway smooth muscle

J Pharmacol Exp Ther

Beta2-Agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D

PLoS One

In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor

J Pharmacol Exp Ther

Phosphodiesterase isozymes modulating inherent tone in human airways: identification and characterization

Am J Physiol

The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C(4)-induced contractions in passively sensitized human airways

Br J Pharmacol

A major functional role for phosphodiesterase 4D5 in human airway smooth muscle cells

Am J Respir Cell Mol Biol