Counterpoint: Alterations in airway smooth muscle phenotype do not cause airway hyperresponsiveness in asthma

Abstract

Point:CounterpointCounterpoint: Alterations in airway smooth muscle phenotype do not cause airway hyperresponsiveness in asthmaPeter D. Paré, and Wayne MitznerPeter D. ParéDepartment of Laboratory Medicine and Pathology University of British Columbia, and Wayne MitznerSchool of Public Health Division of Physiology Johns Hopkins UniversityPublished Online:01 Sep 2012https://doi.org/10.1152/japplphysiol.00483.2012aMoreSectionsPDF (176 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat We have been assigned the task of showing that “alterations in airway smooth muscle phenotype DO NOT cause the airways hyperresponsiveness of asthma.” In the following paragraphs we will briefly review the overwhelming lack of evidence that any fundamental change in the intrinsic properties of ASM are at the basis of airway hyperresponsiveness. It is with considerable empathy that we view the fruitless mission of our less mature and experienced colleagues who must attempt to incriminate the otherwise honorable (albeit vestigial) ASM!We have no argument with the obvious fact that ASM contraction is involved in the phenomenon termed airway hyperresponsiveness (AHR), which we define as excessive or exaggerated airway narrowing in response to agents that directly or indirectly stimulate airway smooth muscle contraction. Airway hyperresponsiveness is characterized by an increase in the magnitude of airway narrowing that can be achieved accompanied by a lowering of the intensity of the stimulus required for any degree of narrowing. Excessive airway narrowing can come about because of greater airway smooth muscle shorting and/or because a given amount of smooth muscle shortening causes a greater effect on the airway lumen. Although both of these mechanisms can clearly contribute to AHR, our thesis is that they do so, not because there is a fundamental change in ASM, but because the milieu of the ASM, the structure of the airways, and/or the relationship of the airways to the lung parenchyma in which they are embedded is altered. We recognize that an increased mass of smooth muscle can be part of the structural alterations that increase maximal airway narrowing but contend that this increased mass does not qualify as a change in smooth muscle phenotype. Such a claim would be analogous to claiming that obesity is caused by a phenotypic change in the adiopocyte. The increased mass of muscle is a phenotypic change in the airway or in the asthmatic subject … not in the ASM.Undoubtedly changes in smooth muscle phenotype could contribute to airway hyperresponsiveness. For example, more narrowing could occur if the muscle was able to generate more force per unit area (stress) or was capable of shortening faster. We simply claim that there is no reliably reproducible evidence that these phenotypic changes are present in asthmatic ASM. The relevant phenotypic variables on which we base our conclusions are discussed next.Maximal ASM stress.Although some early studies suggested that ASM from asthmatics was stronger (1, 7), the bulk of the data (2, 10, 11, 14, 31) support a conclusion that maximal force-generating capacity does not differ between asthmatic and non-asthmatic ASM [summarized in McParland and coworkers' review (23)]. Increased maximal stress per smooth muscle cell could be caused by increased effectiveness of the contractile machinery, an enhancement in excitation/contraction coupling (25). A molecular phenotypic change that could achieve this would be an increase in the activity of some specific enzymes such as myosin light chain kinase. Although such changes have been reported by some (4, 19, 20), they have not been supported by other investigators (22, 32). In apparent support of phenotypic changes, Matsumoto et al. (22) showed that cultured airway smooth muscle cells from asthmatics contracted collagen gels to a greater extent than non-asthmatic cells over a 12-h period. Although this is a clever experiment with fascinating results, it begs the question of what does gel contraction over 12 h by isolated cultured ASM cells have to do with the acute airway narrowing seen during measurement of airway responsiveness or an asthmatic attack? Gel contraction is a measure of the ability of fibroblasts or myofibroblasts to effect wound healing, and thus this observation is likely more relevant to airway wall remodeling than to bronchoconstriction.ASM shortening velocity.An increase in ASM shortening velocity could contribute to AHR (8), and it is possible that a change in ASM phenotype could lead to an increased shortening velocity. In fact Ma et al. (20) showed that collagenase-treated single cells obtained from asthmatic subjects by bronchial biopsy and studied in vitro shortened ∼15% faster than similarly obtained cells from non-asthmatic subjects. However, it is not clear how to relate this result to airway narrowing in vivo, because the maximal shortening achieved in these cells was only 25–40% of initial length, which is substantially less that the maximal shortening capacity of human airway smooth muscle strips (∼75%) (13). In addition, Chin et al. (14) recently constructed force velocity curves of ASM strips from asthmatics and nonasthmatics and showed no significant difference.Other ASM phenotypic changes.We want to be clear that we are not arguing that there are no phenotypic changes in the airway smooth muscle from asthmatic subjects. Elegant studies have shown that asthmatic airway smooth muscle is more proliferative (18, 21, 26, 30), shows altered calcium handling (21), exhibits increased mitochondrial biogenesis (30), shows altered secretion of matrix proteins (17), has enhanced migratory capacity (3), and synthesizes and secretes excessive inflammatory cytokines and growth factors (9, 12, 15, 27). What we are arguing is that these phenotypic changes have not been shown to directly contribute to airway hyperresponsiveness, i.e., to translate into greater force generation or shortening velocity in vivo. In fact many of the phenotypic changes in ASM cells in asthma (e.g., matrix synthesis, migration, etc.) suggest that the muscle reverts to a more synthetic, myofibroblast-like (and perhaps even less contractile) phenotype under the influence of airway inflammation.We can figuratively hear our worthy opponents rebutting these hard data with a plaintive, “OK, if a change in ASM phenotype is not at the basis of AHR, what is?!!?” That is, because they now realize that their position has been shattered, they are begging us, their even worthier opponents, to provide them with the answer. This is a typical response of defeated warriors. Unfortunately the format of this debate does not provide enough space to detail the many alternate mechanisms by which exaggerated airway narrowing may come about in asthma. However, Fig. 1 illustrates the different possibilities, that have been summarized in a recent review (6).Download figureDownload PowerPointBriefly, exaggerated airway narrowing can occur due to increased smooth muscle shortening and/or an exaggerated effect of a given amount of smooth muscle shortening. Increased airway wall thickness due to edema, matrix deposition, cell hypertrophy, and hyperplasic or hyperemia can amplify the effect of smooth muscle shortening, and there is ample evidence that such airway remodeling occurs in asthma. Increased secretions within the airway lumen can have the same amplifying effect, and the hypersecretion of viscous mucus is a well recognized but underemphasized feature of asthma. The degree to which the ASM shortens and narrows the airway lumen is also critically dependent on the loads against which the ASM must act. There is evidence that the accumulation of fluid and tissue external to the smooth muscle layer can attenuate the transmission of force generated by cyclic breathing maneuvers to the ASM, essentially unloading the muscle. Airway smooth muscle's ability to shorten is also dependent on its position on the length-tension curve. A lengthening of the muscle as might occur with airway remodeling may render it more contractile. Additionally, the airway smooth muscle length-tension curve is not a fixed function and can be shifted to longer or shorter lengths based on length history. Thus any process that shortens muscle could cause it to adapt to the shorter length, and by adapting at that length it would have the capacity to shorten excessively. There is increasing evidence that a failure of ASM to relax following the stretch induced by tidal breathing and deep inspirations is a fundamental difference between asthmatics and nonasthmatics, and this faulty relaxation could contribute to AHR (28). Although this could be blamed on a phenotypic change in the muscle, there is no evidence for it, and it is more likely due to the nonmuscle remodeling, which is well known to occur in asthma. An additional possibility to explain AHR without incriminating ASM is the heterogeneity of airway remodeling, which is present in asthma. Thorpe and Bates (29) and Gillis and Lutchen (16) have used sophisticated modeling to illustrate that heterogeneity by itself can contribute to AHR in the whole lung in vivo. Finally a recent defender of ASM has suggested that it is innocent but badly behaved because of the company it keeps (5). The idea that the milieu influences ASM behavior is not a new one, but the demonstration by Bosse et al. (5) that the presence of low levels of inflammatory spasmogens can cause the phenomenon of force adaption offers a possible explanation for this environmental effect. Of course the very notion that it is even possible for the ASM to be able to do anything good is really no longer a matter for debate (24).Oyez! Oyez! In the opinion of this scientific jury of two, counterappointed by the Journal of Applied Physiology, we find the ASM not guilty of phenotypic changes contributing to the airway hyperresponsiveness of asthma. On the basis of the weak and inconsistent evidence presented by the scientific community, the obvious lack of a smoking gun, and the fact that there are so many other likely suspects who could be equally responsible for the crime, the ASM is hereby proclaimed innocent. 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McFawn15 May 2013 | Journal of Applied Physiology, Vol. 114, No. 10 More from this issue > Volume 113Issue 5September 2012Pages 839-842 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00483.2012aPubMed22942220History Published online 1 September 2012 Published in print 1 September 2012 Metrics