Airway smooth muscle in asthma: just a target for bronchodilation?

Abstract

Airway smooth muscle (ASM) has long been recognized as the main cell type responsible for bronchial hyperresponsiveness. It has, thus, been considered as a target for bronchodilation. In asthma, however, there is a complex relationship between ASM and inflammatory cells, such as mast cells and T lymphocytes. Moreover, the increased ASM mass in asthmatic airways is one of the key features of airway remodeling. This article aims to review the main concepts about the 3 possible roles of ASM in asthma: (1) contractile tone, (2) inflammatory response, and (3) remodeling.

Figure 1. Excitation-contraction coupling in airway smooth muscle

Effects of pro-inflammatory cytokines and β₂-adrenergic receptor agonists on excitation-contraction coupling in ASM cells. Contractile agonists activate receptors that influence intracellular signaling, affecting calcium homeostasis and sensitization as well as the function and expression of GPCRs and CD38. Inflammatory cytokines bind to receptors and modulate calcium homeostasis by increasing expression of CD38 and increasing Ca²⁺ release from the sarcoplasmic reticulum. Inflammatory cytokines such as IL-13, IL-1β and TNF-α also increase Rho kinase activity to modulate the calcium sensitization pathways. β₂-adrenergic receptor agonists regulate calcium homeostasis and calcium sensitization by inhibiting RhoA activation, Ca²⁺ release from the sarcoplasmic reticulum, and actin-myosin crossbridging. cADPR, cyclic ADP ribose; CaM, calmodulin; DAG, diacylglycerol; GEF, guanine exchange factor; GPCR, G-protein–coupled receptor; IP₃, inositol tri-phosphate; MLC, myosin light chain; MLCK, myosin light chain kinase; PIP₂, phophatylinositol 4,5 biphosphate; PLC, phospholipase C; RyR, ryanodine receptor; SR, sarcoplasmic reticulum; β₂AR, β₂-adrenergic receptor.

Figure 2. Airway smooth muscle - mast cell interaction

Airway smooth muscle (ASM) can adhere to mast cell through cell-cell direct interaction involving cell adhesion molecule 1 (CADM1) and through cell-extracellular matrix interaction involving type I collagen and both CD44 and CD51.