Chronic activation in shortened airway smooth muscle: a synergistic combination underlying airway hyperresponsiveness?

Airway smooth muscle (ASM) in individuals with asthma is continuously stimulated by spasmogens released as part of chronic airway inflammation. This chronic submaximal stimulation of ASM produces "tone," which may or may not narrow airways sufficiently to induce respiratory symptoms. However, when coupled with a bronchoprovocative challenge with a nonspecific contractile agonist, this increased tone could contribute to the manifestation of airway hyperresponsiveness (AHR). In this study, we examined the effect of chronic acetylcholine (ACh) exposure at different muscle lengths to gain insights into the consequence of increased tone on the mechanical properties of ASM. The total force (the ACh-induced tone plus active force induced by a second stimulus-electric field stimulation [EFS]) increased immediately after induction of muscle tone, and increased further over time in the presence of the tone in a process termed "force adaptation." The phenomenon of force adaptation was observed over a wide range of muscle lengths and did not prevent length adaptation when the muscle was adapted to the tone before being subjected to a length change, suggesting that both length and force adaptations can occur sequentially and in an independent fashion in the same tissue. Together, these results suggest that adaptation of ASM to shortened length in the presence of muscle tone produced a condition that favored excessive force generation in response to a second stimulus (herein EFS) at reduced muscle length. In vivo these changes will be translated into excessive airway narrowing in response to naturally occurring and pharmacological bronchoconstricting stimuli.