Airway Hyperresponsiveness, Remodeling, and Smooth Muscle Mass

Abstract

We quantified the effects of airway wall remodeling upon airway smooth muscle (ASM) shortening. Isolated ASM from sheep was attached to a servo-controller that applied a physiologic load. This load could be altered to reflect specified changes of airway wall geometry, elasticity, parenchymal tethering, transpulmonary pressure (P L ), and fluctuations in P L associated with breathing. Starting at a reference length (L ref ), ASM was stimulated with acetlycholine and held at constant P L of 4 cm H 2 O for 2 h. When all compartments were thickened to simulate the asthmatic airway but P L was held fixed, ASM shortened much more than that in the normal airway (to 0. ). These findings confirm the long-held conclusion that increased muscle mass is the functionally dominant derangement, but mechanisms accounting for this conclusion differ dramatically from those previously presumed. Furthermore, increased ASM mass explained both hyperresponsiveness and the failure of a DI to relax the asthmatic airway.Keywords: remodeling; asthma; hyperresponsiveness Asthma is characterized by airways that constrict too easily (airway hypersensitivity) and too much (airway hyperresponsiveness, AHR) (1). It is the excessive airway narrowing associated with AHR, rather than the hypersensitivity, that accounts for the morbidity and the mortality that is attributable to the disease (2-4). AHR is thought to arise as a result of ongoing and irreversible remodeling of the airway wall (2, 5-10). Among the various factors that come into play, AHR might be accounted for either by increased mass of airway smooth muscle (ASM) or by decreased load against which the ASM must contract, but it is widely believed that increased ASM mass is the main culprit (11-13). This important conclusion is based mainly upon theoretical considerations, however, wherein structural evidence has been incorporated into detailed mathematical models of airway narrowing (11,12,14).While these mathematical models incorporated the best information then available, they rested upon pivotal assumptions that were shown subsequently to be erroneous (15-18). In particular, muscle was represented by its isometric force-length relationship. But being a characterization of muscle contraction in purely static circumstances, such a description is intrinsically incapable of broaching issues involving smooth muscle dynamics as occur during tidal breathing and deep inspirations (DIs). For example, as early as 1859 Salter (19) reported the following:. . .[bronchial] spasm may be broken through, and the respiration for the time rendered perfectly free and easy, by taking a long, deep, full inspiration. In severe asthmatic breathing this cannot be done; but in the slight bronchial spasm that characterizes hay asthma I have frequently witnessed it. It seems as if the deep inspiration overcame and broke through the contracted state of the air-tubes, which was not immediately re-established.Subsequently we came to learn that of all innate agencies of bronchodilation the most potent of all is a ...

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

“…These reversible or partially irreversible modifications alter the composition of the airway wall, contributing to luminal diameter narrowing in asthma (13,45). Furthermore, studies suggest that alterations in airway structural cell size or accumulation can influence AHR (46,47). In this section, we identify mechanisms underlying the fibrosis, differentiation, proliferation, and apoptosis involved in TGF-b1-induced airway structural cell remodeling.…”

Mechanotransduction, asthma and airway smooth muscle

“…Findings obtained thus far with a hybrid approach of a freshly dissected airway smooth muscle and a virtual human asthmatic airway have reinforced the long-held conclusion that the functionally dominant derangement accounting for airway hyperresponsiveness is increased smooth muscle mass [21,38]. The main mechanisms underlying airway hyperresponsiveness, however, are intrinsically dynamic, and are therefore unaccounted for in previous theoretical models, which are intrinsically static.…”

“…Recently, Oliver et al used the same hybrid approach to study the sensitivity of muscle length to changes of tidal volume, muscle activation, and thickening of airway wall compartments [38]. They found that smooth muscle mass is the functionally dominant cause for excessive airway narrowing (Fig.…”

“…Muscle stretch due to tidal breathing and deep inspirations is a potent inhibitor of active muscle force [11], as a result of the mechanotransduction processes explained above. If muscle mass becomes too large, however, then the muscle and with it the airway stiffens and therefore stretches less, and because it stretches less it stiffens even more, and so on [38]. This positive feedback prevents the smooth muscle to become fully activated and hence prevents it to fully constrict the airways in the non-asthmatic, but in the asthmatic, it causes the smooth muscle to collapse to a fully activated state and to become so stiff that tidal breathing and deep inspirations can no longer inhibit active muscle force.…”

Airway Smooth Muscle in Asthma Symptoms: Culprit but Maybe Innocent

“…Nevertheless, these length oscillations are known to decrease ASM stiffness, even during supra-maximal activation with ACh (66,84,128,198). Importantly, the maximal force-generating capacity of ASM during or immediately following these oscillations is also reduced (66,84,85,128,186,198,242). The decline in isometric force that ensues length oscillations has been shown to be proportional to the amplitude and the duration of the stretch, but not to the frequency (242).…”