© 2004 American Thoracic Society
Asthma—More Muscle Cells or More Muscular Cells?University of Sydney Sydney, New South Wales, Australia The role of the airway smooth muscle in the pathophysiology of asthma has fascinated researchers since the early part of the 20th century. Huber and Koessler (1) commented on the fact that there was more muscle in the airways of patients with asthma and there has been almost complete agreement on this in subsequent studies (2–5). In this issue of the Journal (pp. 1001–1006), Woodruff and colleagues (6) have reported their findings on a study that used some of the latest techniques to address the essential question: what's wrong with the muscle in asthma? Some of their findings are in line with those of previous studies and others are in direct contradiction. Given that the airways of patients with asthma narrow within minutes to stimuli as diverse as exercise, allergens, cold air, and so on, it stands to reason that this is primarily a function of airway smooth muscle contraction. Support for this is evident from the fact that ß adrenoceptor agonists, which we know produce relaxation of airway smooth muscle via stimulation of their relevant receptors, reverse this bronchoconstriction. Thus it is logical to assume that there is something radically wrong with the muscle in a patient with asthma. The big questions that surround the muscle have now crystallized to: Is the muscle increased in amount and hypercontractile? Or is the muscle just increased and, if there is just more of it, is this a result of hyperplasia (an increase in cell number) or hypertrophy (an increase in cell size)? Why is it of value to know the answers to these questions? The importance lies in the fact that, although most patients with asthma respond well to currently available therapy, there remains a group in whom there are structural changes (remodeling) that may be irreversible and that may require different or additional therapeutic approaches. The increase in smooth muscle mass is considered an important component of these changes and it is even conceivable that an inherent abnormality in the airway smooth muscle cell (7) could be the instigator of the remodeling process. The mechanisms underlying the development of hypertrophy and hyperplasia are likely to be different and, this being the case, then different means of intervention or prevention will be appropriate. When individual muscle cells are digested from biopsies taken from patients with asthma (8), these cells contract more quickly and contain a greater amount of myosin light chain kinase that also exhibits greater activity. On the other hand, Woodruff and coworkers (6) found no evidence of any increase in a range of relevant contractile proteins including myosin light chain kinase. Pharmacological studies of resected bronchus from patients with asthma and subjects free of asthma are rare and the few that have been performed have uncovered no evidence of hypercontractility in vitro (9). The fact that isometric tension, however, was measured, as opposed to velocity of shortening, could have influenced these findings. Woodruff and coworkers (6) also found no evidence of hypertrophy, which differs from the results of Ebina and coworkers (4). These authors found that increased muscle mass occurred in two different patterns: the first was mainly hypertrophy, and the second was principally hyperplasia in the proximal airways. Recently, to overcome the difficulties in obtaining human tissue for study, Zhou and coworkers (10) immortalized human airway smooth muscle cells and were able to demonstrate hypertrophy and increased contractile protein expression. Benayoun and coworkers (11) found a combination of hypertrophy and increased smooth muscle proteins. So how do we explain these differences? Perhaps it is a question of the timing of measurement. Benayoun and coworkers (11) studied patients with severe asthma, whereas Woodruff and coworkers (6) excluded patients who had had a recent exacerbation, thereby perhaps missing what could have been a transient increase in muscle gene expression. Woodruff and colleagues (6) found a nearly two-fold increase in the number of airway smooth muscle cells in the airways of patients with asthma. They conclude that this is consistent with the findings of Johnson and coworkers (7) that airway smooth muscle cells cultured from subjects with asthma proliferate at twice the rate of those derived from subjects without asthma. They regard this as a rationale for research into identifying specific proliferative mediators that could be targets for intervention. Because the increased proliferative capacity of asthmatic airway smooth muscle cells, however, is demonstrable in isolation in vitro, these mediators would need to be derived from the muscle cell itself for this to be true. Indeed, recently it has become apparent that the muscle cell in vitro is capable of secreting a large number of potent cytokines, proteases, and extracellular matrix proteins. Some of these, such as connective tissue growth factor, are released in greater amounts from asthmatic airway smooth muscle than from control cells (12) while levels of others, such as prostaglandin E2, are decreased (13). Thus there is a body of evidence accumulating for an intrinsic abnormality in the airway smooth muscle cell. Granted these studies were conducted in an artificial environment, namely cell culture, but cells from both patients with asthma and subjects without asthma were subject to the same conditions and differences were still apparent. One of the factors that it was not possible to consider in the study of Woodruff and coworkers (6)—because they studied muscle isolated in bundles using laser capture microdissection—is the influence of the extracellular matrix on muscle function. Johnson and coworkers (14) have recently demonstrated that although conditioned medium from asthmatic airway smooth muscle cells does not increase the growth rate of nonasthmatic cells, growing nonasthmatic cells on a matrix bed produced by asthmatic cells does. This highlights the important and intimate relationship between the muscle and its matrix bed. So which is it: more cells, more contraction, or just bigger cells? These are important questions that require more studies of tissues and cells from patients with asthma of different severity. Only then shall we be able to develop new strategies to further alter the clinical course of asthma. FOOTNOTES Conflict of Interest Statement: J.L.B. has no declared conflict of interest. REFERENCES
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