Role of Airway Smooth Muscle in Inflammation Related to Asthma and COPD

Abstract

Airway smooth muscle contributes to both contractility and inflammation in the pathophysiology of asthma and COPD. Airway smooth muscle cells can change the degree of a variety of functions, including contraction, proliferation, migration, and the secretion of inflammatory mediators (phenotype plasticity). Airflow limitation, airway hyperresponsiveness, β₂-adrenergic desensitization, and airway remodeling, which are fundamental characteristic features of these diseases, are caused by phenotype changes in airway smooth muscle cells. Alterations between contractile and hyper-contractile, synthetic/proliferative phenotypes result from Ca²⁺ dynamics and Ca²⁺ sensitization. Modulation of Ca²⁺ dynamics through the large-conductance Ca²⁺-activated K⁺ channel/L-type voltage-dependent Ca²⁺ channel linkage and of Ca²⁺ sensitization through the RhoA/Rho-kinase pathway contributes not only to alterations in the contractile phenotype involved in airflow limitation, airway hyperresponsiveness, and β₂-adrenergic desensitization but also to alteration of the synthetic/proliferative phenotype involved in airway remodeling. These Ca²⁺ signal pathways are also associated with synergistic effects due to allosteric modulation between β₂-adrenergic agonists and muscarinic antagonists. Therefore, airway smooth muscle may be a target tissue in the therapy for these diseases. Moreover, the phenotype changing in airway smooth muscle cells with focuses on Ca²⁺ signaling may provide novel strategies for research and development of effective remedies against both bronchoconstriction and inflammation.

Keywords: Allosteric effect; Ca2+signaling; Large-conductance Ca2+-activated K+ channels; Phenotype change; Rho-kinase; β2-adrenergic receptors.