Airway hyperresponsiveness; smooth muscle as the principal actor

Abstract

Airway hyperresponsiveness (AHR) is a defining characteristic of asthma that refers to the capacity of the airways to undergo exaggerated narrowing in response to stimuli that do not result in comparable degrees of airway narrowing in healthy subjects. Airway smooth muscle (ASM) contraction mediates airway narrowing, but it remains uncertain as to whether the smooth muscle is intrinsically altered in asthmatic subjects or is responding abnormally as a result of the milieu in which it sits. ASM in the trachea or major bronchi does not differ in its contractile characteristics in asthmatics, but the more pertinent peripheral airways await complete exploration. The mass of ASM is increased in many but not all asthmatics and therefore cannot be a unifying hypothesis for AHR, although when increased in mass it may contribute to AHR. The inability of a deep breath to reverse or prevent bronchial narrowing in asthma may reflect an intrinsic difference in the mechanisms that lead to softening of contracted ASM when subjected to stretch. Cytokines such as interleukin-13 and tumor necrosis factor-α promote a more contractile ASM phenotype. The composition and increased stiffness of the matrix in which ASM is embedded promotes a more proliferative and pro-inflammatory ASM phenotype, but the expected dedifferentiation and loss of contractility have not been shown. Airway epithelium may drive ASM proliferation and/or molecular remodeling in ways that may lead to AHR. In conclusion, AHR is likely multifactorial in origin, reflecting the plasticity of ASM properties in the inflammatory environment of the asthmatic airway.

Keywords: Airway epithelium; Airway hyperresponsiveness; asthma; smooth muscle.

Figure 1.. Mechanical determinants of airway narrowing.

Airway narrowing is favored by enhanced contractility of airway smooth muscle (ASM) and by an increase in mass of ASM. Potent inhibitors of airway narrowing are lung elastic recoil, airway-parenchymal interdependence, and oscillatory stretches of the ASM caused by breathing movements and intermittent deep breaths.

Figure 2.. The modulation of airway smooth muscle properties by the asthmatic milieu.

Airway smooth muscle (ASM) function is modulated by cytokines such as interleukin (IL)-13 and tumor necrosis factor (TNF)-α that increase intracellular calcium release in response to agonists such as histamine. ASM is triggered to proliferate in vivo by release of epidermal growth factor receptor (EGFR) ligands. The stiffness and composition of the matrix change ASM phenotype and may promote pro-inflammatory properties.