Airway Smooth Muscle as a Target of Asthma Therapy: History and New Directions

Luke J. Janssen; Kieran Killian

Disclosures

Respiratory Research 

In This Article

Abstract and Background

Abstract

Ultimately, asthma is a disease characterized by constriction of airway smooth muscle (ASM). The earliest approach to the treatment of asthma comprised the use of xanthines and anti-cholinergics with the later introduction of anti-histamines and anti-leukotrienes. Agents directed at ion channels on the smooth muscle membrane (Ca2+ channel blockers, K+ channel openers) have been tried and found to be ineffective. Functional antagonists, which modulate intracellular signalling pathways within the smooth muscle (β-agonists and phosphodiesterase inhibitors), have been used for decades with success, but are not universally effective and patients continue to suffer with exacerbations of asthma using these drugs. During the past several decades, research energies have been directed into developing therapies to treat airway inflammation, but there have been no substantial advances in asthma therapies targeting the ASM. In this manuscript, excitation-contraction coupling in ASM is addressed, highlighting the current treatment of asthma while proposing several new directions that may prove helpful in the management of this disease.

Background

Asthma is experienced during the life span of approximately 10% of the population, resulting in morbidity and mortality costing a substantial economic burden on society.[1] The predominant feature of asthma is the discomfort experienced upon breathing in the presence of excessive and inappropriate constriction of the airway smooth muscle (ASM). Although airway inflammation may play an important role in asthma, it is benign in the absence of airway narrowing. The patient is thus predominantly concerned with narrowing of their airways, contributing to an unpleasant increase in the effort required to breathe; in the extreme, this increased effort fails to allow sufficient ventilation, leading to morbidity and even mortality. As such, ASM is ultimately a major target in any management of asthma.

The earliest recorded treatments of asthma included tobacco, indian hemp, sedation (using low doses of chloroform, ether, or opium), ipecacuana, coffee, tea, stramonium lobelia and other less effective agents. These agents express the pharmacological properties of the xanthines, cholinergic blockade, sympathetic stimulation, sedation and direct smooth muscle relaxation. Direct approaches using anti-cholinergics, anti-histamines, anti-leukotrienes, and functional antagonists modulating intracellular signalling pathways (β-agonists and phosphodiesterase inhibitors) followed (section 3.2). These have been used for decades with reasonable success, but patients continue to suffer exacerbations of asthma. Research energies were poured into developing new therapies to treat airway inflammation to prevent rather than treat the active disease. Asthma therapies using immune modulation and anti-inflammatory therapies proved to be so successful that targeting the ASM receded. Better understanding of the mechanisms underlying contraction of ASM is still essential to the management of the active disease. In this manuscript, basic excitation-contraction coupling in ASM is summarized and several new directions to the treatment of abnormal smooth muscle constriction are introduced.

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