Airway smooth muscle modulation and airway hyper-responsiveness in asthma: new cellular and molecular paradigms.
There is growing evidence indicating the existence of a causal relationship between abnormal airway smooth muscle (ASM) function and airway hyper-responsiveness, a poorly understood feature of asthma that can be defined as an excessive bronchospastic response. In recent years, there has been a veritable explosion of articles suggesting that ASM exposed to proasthmatic cytokines can elicit a hyper-responsive state to contractile G-protein-coupled receptor (GPCR) agonists. Aberrant airway responsiveness could result from abnormal calcium signaling, with changes occurring at various levels of GPCR-associated signal transduction. This review presents the latest observations describing novel mechanistic models that could explain the involvement of ASM in airway hyper-responsiveness. This review will discuss the role of ASM in beta(2)-agonist-mediated bronchial hyper-responsiveness and the clinical significance of cell-cell contact between ASM and mast cells recently described to be intimately infiltrated within the ASM tissues in asthmatic patients. The possibility that allergens could trigger airway hyper-responsiveness by directly acting on ASM via activation of immunoglobulin E receptors, FcepsilonRI and FCepsilonRII will also be discussed. These important findings further support the notion that targeting ASM could offer new treatment for many features of asthma, including airway hyper-responsiveness. Future therapeutic intervention includes: the prevention of ASM-inflammatory cell physical and/or functional interaction, the inhibition of Immunoglobulin E receptor-dependent signal transduction, and the abrogation of cytokine-dependent pathways that modulate receptor-associated calcium metabolism.
Amrani
Yassine
Y
University of Pennsylvania Medical Center, Pulmonary, Allergy and Critical Care Division, Department of Medicine, BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA. amrani@mail.med.upenn.edu