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(Chest. 2003;123:392S-398S.)
© 2003 American College of Chest Physicians

Actin Dynamics*

A Potential Integrator of Smooth Muscle (Dys-)Function and Contractile Apparatus Gene Expression In Asthma

Julian Solway, MD; Shashi Bellam, MD; Maria Dowell, MD; Blanca Camoretti-Mercado, PhD; Nickolai Dulin, PhD; Darren Fernandes, PhD; Andrew Halayko, PhD; Pawel Kocieniewski, BS; Paul Kogut, MD; Oren Lakser, MD; Hong Wei Liu, MD; Joel McCauley, BS; John McConville, MD and Richard Mitchell, PhD

* From the Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL; and Departments of Medicine and Physiology, University of Manitoba, Winnipeg, MB, Canada.

Correspondence to: Julian Solway, MD, University of Chicago, 5841 S Maryland Ave, MC6026, Rm M644, Chicago, IL 60637; e-mail: jsolway{at}medicine.bsd.uchicago.edu


   Parker B. Francis Lecture
TOP
 Parker B. Francis Lecture
Smooth Muscle Mechanics
 Gene Expression
 Implications
 References
 
Airway smooth muscle plays a well-accepted and critical role in the pathophysiology of acute airflow obstruction in asthma patients. When stimulated to contract (naturally, by mediators released within the inflammatory environment of the airway wall, or in the laboratory, by the inhalation of methacholine or histamine), the shortening airway muscle bands not only directly narrow the airway lumen, but they also squeeze circumferentially on the submucosa and epithelium, deforming these tissues into folds that invade the already compromised open space for airflow. Together with the excessive mucous secretions that are typical of asthma, these consequences of airway smooth muscle contraction synergize to effect substantial airflow obstruction, which is the hallmark of an acute asthma attack. Clearly, understanding how asthmatic airway smooth muscle accomplishes this hurtful role is worthwhile. The thesis of this article is that actin filament dynamics play key regulatory roles in two aspects of smooth muscle pathobiology (ie, mechanical behavior and gene expression) that likely contribute to the pathophysiology of this disease.


   Smooth Muscle Mechanics
TOP
 Parker B. Francis Lecture
 Smooth Muscle Mechanics
Gene Expression
 Implications
 References
 
It is well-established that the airways of asthmatic individuals respond to constrictor agonists at much reduced concentrations compared with those of healthy subjects, and the maximum airflow obstruction that can be induced by these agents is characteristically much greater in asthmatic patients than in healthy individuals.1 Together, the increased sensitivity and greater maximal response to treatment with bronchoconstrictors that have been demonstrated by asthmatic airways in vivo are termed bronchial hyperresponsiveness (BHR). Although it is reasonable to speculate that asthmatic BHR might stem from increased numbers of constrictor agonist receptors, from intracellular signaling defects, or from the alteration of other aspects of contractile apparatus activation, the weight of evidence to date2 3 4 5 6 7 8 (almost completely from static, isometric studies of smooth muscle in vitro) has suggested that this is not the case. (For completeness, it should be noted that the unique constrictor response of asthmatic airways to adenosine is thought to reflect the differential activation of adenosine receptors on mast cells in asthmatic airways.4 9 Also, model studies do suggest that the increased force that should accompany increased muscle mass may be an important contributor to asthmatic BHR.10 ) These findings speak against the likelihood that the enhanced activation of contraction represents the key abnormality underlying asthmatic BHR. Instead, an alternative potential explanation is suggested by studies that examine the influence of transient airway stretch on airway caliber.

First, let us recognize that taking a deep breath to total lung capacity (TLC) stretches the airways. This occurs because intrapulmonary airways are embedded within lung parenchyma. As the surrounding alveoli are inflated, alveolar walls exert radial traction on the airway adventitia, providing force that stretches the airway wall and distends the bronchial lumen (Fig 1 ). [This stretching provides the basis for the reporting of specific airway conductance (SGaw) by pulmonary function laboratories in their effort to "correct for" lung volume-induced airway caliber changes. SGaw = 1/(Raw*VL), where Raw is airway resistance and VL is the lung volume at which it was measured.] Importantly, Brown and colleagues11 recently used high-resolution CT scans to demonstrate that a deep inhalation to TLC stretches the airways of both healthy and asthmatic subjects equivalently. Furthermore, this remains true even in the presence of similar degrees of methacholine-induced bronchoconstriction. What is different, however, between asthmatic individuals and normal individuals lies in what happens after a deep inhalation-induced airway stretch, after the subjects have returned to ordinary breathing volumes (ie, functional residual capacity).



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  		Figure 1. Inflation of the lung from low lung volumes (left) to high lung volumes (right) increases tension within the alveolar walls (black lines), which in turn exerts radial traction on the walls (concentric light and dark rings) of airways embedded within the lung parenchyma. As a result of this traction, lung inflation stretches the airway wall circumferentially.

 
In a seminal study, Fish et al12 had atopic nonasthmatic (control) subjects or atopic asthmatic subjects breathe methacholine at doses that caused moderate reductions in SGaw, then tracked changes in SGaw after each subject took a deep breath to TLC followed by a return to breathing near functional residual capacity. In the non-asthmatic subjects, deep inspiration rapidly reversed bronchoconstriction, returning SGaw to near pre-methacholine inhalation values. This deep breath-induced net bronchodilation then slowly wore off over the course of about 1 min. In marked contrast, there was no appreciable bronchodilation observed after asthmatic subjects had taken deep breaths. This striking difference in the effect of a deep breath on induced bronchoconstriction in asthmatic patients vs healthy subjects remains one of the most salient distinguishing features of asthma pathophysiology. How could this occur?

There are at least three potential mechanisms that could account for this observation. First, it might be that after being stretched, asthmatic muscle within the airway wall (presumably still stimulated to contract) shortens again with a faster velocity of shortening than does smooth muscle within the airways of healthy individuals.13 14 If so, then airway narrowing could be reestablished quickly, obviating the longer persisting, deep breath-induced bronchodilation seen in healthy subjects whose muscle (in this proposed construct) shortens more slowly. While there has been no direct demonstration that this mechanism operates in humans with asthma, increased velocity of shortening has been documented in airway muscle strips from allergen-sensitized animals15 16 17 18 and in human airway muscle strips incubated with serum from atopic individuals.19 There also has been a report20 that single smooth muscle cells that have been isolated from endobronchial biopsy specimens of asthmatic patients contract with greater velocity and to a greater extent than do corresponding myocytes from the airways of healthy subjects. As such, increased velocity of shortening remains a tenable explanation for the rapid post-deep inspiration restoration of bronchoconstriction observed in asthmatic people.

Second, it is conceivable that stretching asthmatic airway muscle induces its subsequent contraction, a phenomenon known as a myogenic response to stretch. While we are unaware of studies of myogenic responses in muscle from asthmatic subjects, airway muscle strips from healthy humans develop a myogenic response to stretch after incubation with atopic human serum.21

Third, perhaps smooth muscle within the bronchial walls of asthmatic patients exhibits an overly elastic behavior that is not found normally. We propose that the persistent bronchodilation induced by deep inhalation in healthy individuals reflects a plastic deformation of contracted airway smooth muscle, which we view as the normal behavior. In this view, methacholine-contracted normal airway smooth muscle behaves like a taffy candy bar; that is, when stretched forcibly, it remains lengthened, reshortening after the release of the stretching force only slowly and partially. In contrast, contracted asthmatic airway smooth muscle might respond to stretch by elastic deformation, like a rubber band. The rubber band lengthens while a stretching force is being applied, but it resumes its original (short) length as soon as the stretching force is released. Since, to our knowledge, there is no evidence for or against this proposed abnormality in asthmatic airway smooth muscle, it seems incumbent on us to suggest a mechanism that might plausibly lead to elastic responses (in asthmatic patients) vs plastic responses (in healthy subjects) to forced elongation.

First, we must note that a considerable body of evidence supports the notion that normal airways exhibit mechanical plasticity. Muscle strips that are contracted in vitro develop much more force at a given length, prior to being stretched beyond that length and allowed to reshorten to the original length, than they generate after the stretch.22 Furthermore, this behavior appears to influence airway constrictor responsiveness in vivo. Mechanically ventilated rabbits that were given a dose of IV methacholine that causes substantial elevation of Raw while they were apneic, instead exhibited partially or completely ablated constrictor responses to the same methacholine dose while breathing at ordinary or large tidal volumes, respectively. Bronchoconstrictor dose-response curves are shifted to the right during hyperpnea in both guinea pigs and people, and the deep breathing of hyperpnea suppresses hyperpnea-induced bronchoconstriction in guinea pigs until the cessation of hyperpnea. Together, these results demonstrate that normal airways behave plastically and that plastic behavior reduces the apparent bronchial constrictor responsiveness. Mechanisms previously proposed to explain the normal mechanical plasticity of smooth muscle include stretch-induced changes in the attachment of cytoskeleton to the cell membrane at cell adhesion sites,23 24 modulation of the interactions between actin and myosin filaments,25 26 and adjustment of myosin filament length during contraction.27 28 29

How then could mechanical plasticity be reduced in asthma? The mechanism that we propose is that contractile actin filaments might be longer in asthmatic patients than in healthy individuals. The complex regulation of actin filament length (Fig 2 ) provides several potential ways in which the inflammatory environment of smooth muscle in asthmatic airways might promote the accumulation of longer filaments. In general, actin filament length is regulated by the balance of the addition of free actin monomers (which are usually faster at the "barbed end" than at the "pointed end" of the actin filament) vs the loss of actin monomers from either filament end, or from (previously) internal sites along the actin chain after filament severing. Monomer addition is enhanced by higher free G-actin monomer concentrations,30 uncapped filament ends,31 32 and greater profilin activity,33 with the latter promoted by interaction with proline-rich motifs in Wiskott-Aldrich Syndrome (WASP), ezrin, vasodilator-stimulated phosphoprotein, and mDia proteins.34 35 36 Note that mDia proteins are stimulated to increase profilin actin-presenting activity by the intracellular signaling intermediate RhoA,37 38 39 the activity of which is in turn regulated by a number of contractile, growth, and inflammatory stimuli. Interestingly, active RhoA (signaling through Rho kinase then LIM kinase) also inhibits the depolymerization of actin by cofilin.40 41 Other factors that modulate actin filament length include gelsolin,42 which can sever actin filaments, actin side-binding proteins (like tropomyosin) that stabilize actin filaments,43 and pointed-end-capping proteins or barbed-end-capping proteins that slow the addition or removal of actin monomers from either end. Tropomodulin31 appears to be a major pointed-end-capping protein, possibly accompanied by smooth muscle leiomodin,44 45 while HSP27,23 46 47 48 gelsolin,42 and the capping protein {alpha}/ß dimer49 all function as barbed-end-capping proteins.



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  		Figure 2. A schematic summary of mechanisms that might regulate F-actin filament length within airway smooth muscle. Although F-actin filaments are thought to extend bidirectionally from dense bodies containing {alpha}-actinin and vinculin, only one filament is shown here, for clarity. Actin filament length represents the net balance of actin polymerization and depolymerization, which in turn are controlled by the several mechanisms discussed in the text.

 
Figure 3 illustrates the mechanism by which we suggest contractile actin filament length alters the plasticity-elasticity balance in smooth muscle. Imagine that contracted airway smooth muscle cells possess multiple myosin filaments acting in mechanical parallel on actin filaments. Then, consider the differential effect of stretching such contracted airway muscle, either when the actin filaments are short (Fig 3 , A) or when they are long (\?\Fig 3 , B). During a substantial stretch of myocytes with short actin filaments, both these and the intercalating myosin filaments must rearrange from their initial parallel configuration into a mechanical series configuration, if the muscle is to be able to contract at all. One important consequence of this rearrangement is that the force that the muscle can generate is substantially reduced. In the schematized illustration shown, three myosin filaments act in parallel to generate force prior to stretch, whereas after stretch and filament series rearrangement there is only one myosin filament generating force (at any cross-section). Thus, stretching a contracted smooth muscle with short actin filaments reduces its force, and the muscle behaves plastically. In contrast, a contracted myocyte with longer actin filaments need not undergo the parallel-to-series reconfiguration detailed above in order to maintain contraction, and so it may not lose force during stretching. Thus, smooth muscle with longer actin filaments should behave less plastically and more elastically.



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  		Figure 3. A proposed model of contractile filament rearrangement during stretching of contracted airway smooth muscle with short actin filaments prior to stretching (left, A) or long actin filaments prior to stretching (right, B). Actin filaments are shown as orange lines, dense bodies are shown as red ovals, barbed-end actin-capping proteins are shown as green crescents, and myosin filaments are shown in blue. Left, A: continued contraction after the stretching of smooth muscle with short actin filaments (eg, as might occur with capped barbed ends) would require a parallel-to-series rearrangment of myosin filaments, which should diminish force and impart plastic behavior. Right, B: continued contraction after stretching of the smooth muscle with long actin filaments (eg, as might occur with uncapped barbed ends) would not require the parallel-to-series rearrangement that is illustrated in A. In this circumstance, greater force could be maintained, and the muscle would behave more elastically. From Dulin et al.77

 
Lakser et al50 recently have provided evidence that could be consistent with the above theory. They found that bovine tracheal muscle strips contracted against a steady load equivalent to 32% of their maximum force shortened to about 58% of their original length, but lengthened to about 77% of their original length when a substantial load oscillation was superimposed on the same mean load. The "tugs" of force applied in this way thus lengthened the muscle strip, partially reflecting only a modest degree of plasticity at baseline in these strips. However, when muscle strips were pretreated with a chemical inhibitor of the p38 mitogen-activated protein kinase (MAPK) signaling enzyme, they exhibited somewhat greater shortening against the steady force (to about 50% of initial length) and clearly greater plasticity (lengthening to about 88% of the initial length). It is well-established that p38 MAPK is an upstream activator of HSP27 phosphorylation,47 and so this result suggests that the phosphorylation state of HSP27 influences airway muscle plasticity. Since HSP27 caps the barbed end of actin only in its unphosphorylated state,51 52 one might infer that in the absence of p38 MAPK inhibition, HSP27 was phosphorylated, actin filaments were less fully capped, and actin filaments might have been longer. These results are consistent with, but do not prove, our notion that longer actin filaments may impart less plastic behavior. We are currently testing this possibility directly in our own laboratory.


   Gene Expression
TOP
 Parker B. Francis Lecture
 Smooth Muscle Mechanics
 Gene Expression
Implications
 References
 
Serum response factor (SRF) is a 67-kd protein that is ubiquitously expressed but is particularly enriched in skeletal, cardiac, and smooth muscles.53 SRF acquired its name with the discovery that it binds (as a dimer) to the DNA sequence 5'-CC[A/T]6GG-3' (which is called a CArG box) within the serum response element of the c-fos gene promoter,54 55 and so confers immediate early activation of c-fos transcription in cultured cells that have been stimulated with serum. In the context of the serum response element, SRF partners with other transcription factors of the Ets family, to activate transcription. However, SRF also plays a critical role in activating the transcription of muscle-specific genes (including smooth muscle {alpha} actin) by binding to one or more CArG boxes within the promoter/enhancer regions of these genes.56 57 In muscle, SRF is thought to partner with other nuclear factors that impart tissue specificity (including GATA factors, Nkx2.5 or Nkx3.1 and others).58 59 60 61 62 Binding of SRF to CArG boxes within these muscle-specific gene promoters is critical for their activation, as the mutation to prevent SRF binding dramatically reduces gene transcription.63 64

In the 1990s, Treisman and coworkers54 65 66 67 and others68 69 reported that the activation of RhoA enhanced SRF-dependent gene transcription, and a role for Rho kinase (a downstream effector of RhoA signaling) was established in this RhoA effect.66 Subsequently, LIM kinase was implicated in RhoA-activated, SRF-dependent muscle gene transcription,70 71 72 and, in light of the profound effect of this signaling pathway on actin cytoskeletal rearrangement, Sotiropoulos et al72 suggested and provided evidence for the notion that free G-actin acted as a negative regulator of SRF-dependent transcription. Their results, along with subsequent studies in vascular smooth muscle from Mack et al73 and studies from our laboratory,74 confirmed that interventions that lowered free G-actin (including those that promoted actin polymerization) also increased SRF-dependent gene transcription, whereas interventions that increased free G-actin (including those that promoted actin filament depolymerization) concomitantly lowered SRF-dependent gene transcription. A recent report75 has suggested that free G-actin may influence SRF-dependent transcription by interacting with another transcription factor, YY1, that sometimes can antagonize the transcription-promoting activity of SRF. Also, results from our laboratory74 have suggested that the state of actin polymerization may regulate the subcellular localization of SRF, with greater G-actin levels associated with a relative shift of SRF from the nucleus to the cytoplasm (where, of course, it cannot promote gene transcription).

There is a well-established overabundance of smooth muscle in asthmatic airways that stems from both hypertrophy and hyperplasia.76 Whatever is the mechanism of excess muscle accumulation, filling the increased muscle volume with contractile apparatus proteins might well require greater than normal activation of contractile apparatus gene expression. If so, then the greater actin filament length that has been postulated in asthma could conceivably lead to lower G-actin levels and to enhanced contractile apparatus gene expression in airway smooth muscle. We are currently testing this possibility.


   Implications
TOP
 Parker B. Francis Lecture
 Smooth Muscle Mechanics
 Gene Expression
 Implications
References
 
Together, these results suggest the possibility that abnormal actin dynamics within airway myocytes could lead to mechanical dysfunction and gene expression abnormalities in asthma. It is important to stress that the actual relevance of this possibility remains unknown. However, the potential integration through actin filament dynamics of two potential (although still unproved) pathogenetic mechanisms in asthma seems worthy of further evaluation.


   Footnotes
 
Abbreviations: BHR = bronchial hyperresponsiveness; MAPK = mitogen-activated protein kinase; Raw = airway resistance; SGaw = specific airway conductance; SRF = serum response factor; TLC = total lung capacity

This work was supported by grants from the National Institutes of Health (HL56399, HL64095), Thoracic Society of Australia and New Zealand, Glaxo-Smith-Kline Center of Excellence, and the LAM Foundation.


   References
TOP
 Parker B. Francis Lecture
 Smooth Muscle Mechanics
 Gene Expression
 Implications
 References
 

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