Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle in the pathogenesis of asthma in which airway hyperresponsiveness, remodelling and inflammation are, at least in part, attributable to airway smooth muscle. Furthermore, how this new view may lead to a change in the phenotyping and treatment of patients with asthma will be discussed.

Decorin, a small leucine-rich proteoglycan with a widespread tissue distribution, is required for the normal fibrillogenesis of collagen in most tissues. Because collagen is important in determining the elastic behavior of the lung, we hypothesized that lung tissue mechanics would be altered in a mutant mouse in which the single decorin gene was abrogated by targeted deletion (Dcn-/-). Complex impedance of the respiratory system was measured in C57Bl/6 mice (Dcn-/- and Dcn+/+) using a small animal ventilator that delivers a volume signal with multiple frequencies to the trachea. A constant-phase model was fit to calculate airway resistance (R(aw)), tissue damping, and tissue elastance. Compliance of the respiratory system (C(rs)) was measured from a pressure volume curve during stepwise deflations. Lungs were excised, and parenchymal tissue strips were mounted in an organ bath for in vitro measurement of tissue impedance and quasistatic length-stress curves. In addition, pulmonary tissue was examined by immunohistochemistry and immunoblotting. In vivo, in the Dcn-/- mice, R(aw) was decreased and C(rs) was increased. Similarly, in vitro, length-stress curves showed increased compliance of the strips in the Dcn-/- mice. These alterations in lung tissue mechanical behavior in Dcn-/- mice support a critical role for decorin in the formation of the lung collagen network.

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Stretch-induced changes in constricted lung parenchymal strips: role of extracellular matrix. F.G. Salerno, A. Fust, M.S. Ludwig. #ERS Journals Ltd 2004. ABSTRACT: Large amplitude oscillations of contracted airway smooth muscle cause relative relaxation of the preparation. However, little is known about the effect of mechanical stretch on distal lung behaviour.Rat parenchymal strips were suspended in an organ bath and attached at one end to a force transducer and at the other end to a servo-controlled lever arm that effected length changes. Mechanical impedance of the strip was measured by applying a complex signal consisting of pseudorandom length oscillations of varying frequencies . A constant phase model was fit to changes in length and tension to calculate tissue damping (G) and elastance (H). Hysteresivity was calculated as G/H. Impedance was measured before and after sinusoidal length oscillation at different amplitudes (1, 3, 10 and 25% of resting length) at a frequency of 1 Hz under baseline conditions and after acetylcholine-induced constriction.Oscillations of 10 and 25% amplitudes significantly decreased the G and H of the lung strip. The effect of length oscillations was no different in control versus constricted strips.These data suggest that in the distal lung, large stretches affect the structural components of the extracellular matrix rather than the contractile elements. Eur Respir J 2004; 23: 193-198 Understanding the mechanisms underlying the effect of a deep inspiration on lung mechanics has implications for the understanding of asthma pathophysiology. Deep inspirations taken before or after a methacholine challenge decrease the bronchoconstrictor response in normal subjects but not in asthmatics [1,2]. Normal subjects, when asked to refrain from taking deep inspirations after a methacholine (MCh) challenge, behave similarly to hyperresponsive subjects [3]. These observations suggest that the protective effect of deep inspirations on airway narrowing is reduced or absent in asthmatics, a characteristic that may differentiate them from normal subjects. Studies in isolated airway smooth muscle (ASM), which attempt to reproduce the in vivo airway response to tidal breathing and deep inspirations, show that ASM constricts less under dynamic conditions [4]. These data suggest that the effect of lung volume fluctuations on airway narrowing comes from alterations in the ASM.An alternative hypothesis is that the differential effect of deep inspiration in asthmatics compared with controls relates to different lung tissue mechanical properties, because of differences in the extracellular matrix or because of effects on airway-parenchymal interdependence. The lung tissue is a viscoelastic material, and, by definition, viscoelastic materials display hysteresis. FROEB and MEAD [5] theorised that airways also display hysteresis, and the relative hysteresis of these two structures would determine the effect of a deep breath on airway calibre because of the mechanical interdependence between airways and the...