Breathing at volumes lower than functional residual capacity (FRC) can induce changes in nonasthmatic airways consistent with the behaviour of asthmatic airways. This study investigated the chronic effect of breathing at volumes lower than FRC on the contractility of airway smooth muscle and myosin light chain kinase (MLCK) content and activity.Sheep of three age groups (neonate, adolescent and adult) had their FRC reduced by y25% for 4 weeks using a leather corset. Contractile responses to carbachol were then recorded in isolated tracheal strips and bronchial rings. MLCK content and activity were assessed by immunoblotting.The rate of stress generation increased in the bronchial smooth muscle of both adult and adolescent but not neonatal corseted sheep: adolescent corseted versus control, 65.0¡4.1 versus 103.4¡7.0 s (to reach 50% maximum stress), respectively; and adult corseted versus control, 57.0¡6.4 versus 93.4¡8.2 s, respectively. This was not due to increases in either bronchial or tracheal smooth muscle amount or MLCK content and activity.The present results indicate that chronic breathing at low lung volumes increases the rate of stress generation in airway smooth muscle. Excessive airway narrowing resulting from airway smooth muscle (ASM) contraction in response to physical and chemical stimuli is a characteristic of asthma. Breathing at volumes lower than functional residual capacity (FRC) can induce changes in nonasthmatic airways that are consistent with the behaviour of asthmatic airways. Animal studies have shown the marked influence of lung volume on ASM function [1][2][3], and in some clinical situations in which patients chronically breathe at lower lung volumes, this has been suggested as being responsible for changes in airway symptoms. This is the case in obese patients in whom there is an increased prevalence of wheezing [4-6] and airway hyperresponsiveness [7,8].The key regulator of the enzymatic pathway involved in smooth muscle contraction is myosin light chain kinase (MLCK), a dedicated protein kinase, with myosin as its only physiological substrate. MLCK regulates smooth muscle contraction by controlling the activity of actomyosin adenosine triphosphatase (ATPase) and in turn the rate of cross-bridge cycling [9,10]. In smooth muscle, it has been shown that the activity of actomyosin ATPase can be viewed mechanically as an index of shortening velocity [11,12]. A number of physiological studies have been performed using sensitised ASM as a model of asthmatic muscle. These studies have shown that sensitised ASM exhibits increased maximal shortening capacity and increased early shortening velocity [13,14]. Further investigations revealed that these observed changes in the contractile response of ASM were a result of an increase in both the amount and activity of MLCK present in the muscle [15][16][17].Another proposed mechanism for the effect of lung volume is ASM plasticity, in which the organisation of the contractile apparatus of the smooth muscle cell is modified to adapt to ...

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The forced oscillation technique (FOT) can be used to determine airway hyperresponsiveness, but the cut-points for changes in respiratory system conductance (Grs) and reactance (Xrs) that define a positive mannitol challenge are not known. Furthermore, the effects of changes in lung volume on these cut-points or on the repeatability of the test are unknown. In 15 non-asthmatic and 52 asthmatic subjects, response to mannitol challenge was measured by Grs and Xrs, using FOT, and by FEV(1). The FOT variables were adjusted for inspiratory capacity (IC) at each dose. Dose response slope (DRS) was used in receiver operator characteristic (ROC) analysis to compare the ability of adjusted and unadjusted DRSGrs and DRSXrs to detect a positive challenge, defined as PD(15)FEV(1) ≤635 mg mannitol. Mannitol challenges were positive in 32 asthmatic and 2 non-asthmatic subjects. Both DRSGrs and DRSXrs detected positive challenges (p < 0.0001 for both), and this was not altered by adjustment for IC for either DRSGrs (p = 0.21) or DRSXrs (p = 0.90). FOT cut-points for a positive challenge were 27% fall in Grs or 0.93 cm H(2)O/L/s decrease in Xrs at 635 mg. Repeatability of DRSGrs (±2.01 doubling doses) and DRSXrs (±1.95dd) was comparable with DRSFEV(1) (±1.67dd) and was not improved by adjustment for IC. Grs and Xrs, measured by FOT, provide a sensitive, repeatable measure of response to mannitol challenge. Adjusting for lung volume does not alter the ability of these variables to detect a positive response or the repeatability of the measurement.

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