Airway Smooth Muscle Dynamics and Hyperresponsiveness: In and outside the Clinic

Abstract

The primary functional abnormality in asthma is airway hyperresponsiveness (AHR)-excessive airway narrowing to bronchoconstrictor stimuli. Our understanding of the underlying mechanism(s) producing AHR is incomplete. While structure-function relationships have been evoked to explain AHR (e.g., increased airway smooth muscle (ASM) mass in asthma) more recently there has been a focus on how the dynamic mechanical environment of the lung impacts airway responsiveness in health and disease. The effects of breathing movements such as deep inspiration reveal innate protective mechanisms in healthy individuals that are likely mediated by dynamic ASM stretch but which may be impaired in asthmatic patients and thereby facilitate AHR. This perspective considers the evidence for and against a role of dynamic ASM stretch in limiting the capacity of airways to narrow excessively. We propose that lung function measured after bronchial provocation in the laboratory and changes in lung function perceived by the patient in everyday life may be quite different in their dependence on dynamic ASM stretch.

Figure 1

From [48]. (a) Lumen pressure fluctuations in isolated bronchial segments (porcine) during tidal volume oscillation before and after a maximal dose of acetylcholine (ACh). Tidal volume oscillations produced a trough-to-peak pressure cycle from 5 to 10 cmH₂O in relaxed airways. Contraction to ACh is seen by the elevation in trough pressure in a closed system. The increase in the amplitude of pressure cycles indicates stiffening of the airway wall to ACh. (b) Sigmoidal dose-response behaviour of ACh-induced increase in airway stiffness. Values are means ± SE (n = 5).

Figure 2

From [60]. Airway narrowing (Δvolume, %) to acetylcholine (ACh) in human bronchial segments. ACh dose-response curves were constructed from measurements of airway narrowing under static conditions (Static, 5 cmH₂O) and during fixed transmural pressure cycles simulating tidal (5 to 10 cmH₂O at 0.25 Hz) and deep inspiration (DI, 5 to 30 cmH₂O). The dynamic pre-DI curve represents airway narrowing before the onset of DI; dynamic DI 0 s, the airway narrowing measured immediately after DI; dynamic DI 60 s, the airway narrowing measured 1 min after DI. DI produced an immediate reduction in maximal airway narrowing (P < 0.001) but not sensitivity. The effects of DI were largely ablated after 1 min. Airway narrowing under static conditions was not different to that prior to DI, suggesting that tidal oscillations alone did not regulate airway narrowing. Values are means ± SE (n = 6).