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Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115
The Unbearable Lightness of Breathing
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The theory of perturbed myosin binding, put forward only recently, states that the tidal action of lung inflations may play a pivotal role in this process (4, 6). Lung inflations strain airway smooth muscle with each breath, and these periodic mechanical strains are transmitted to the myosin head and cause it to detach from the actin filament much sooner than it would have in isometric circumstances. This premature detachment profoundly reduces the duty cycle of myosin, typically by as much as 50-80% of its unperturbed isometric steady-state value, and depresses total numbers of bridges attached and active force to a similar extent. Of the full isometric force-generating capacity of the muscle, therefore, only a small fraction ever comes to bear on the airway during tidal breathing, even when the muscle is activated maximally. In pathological circumstances, however, the tidal strains acting on myosin can become compromised. For example, in the chronically inflamed airway, the peribronchial adventitia thickens (10); this thickening decreases tidal muscle strains and thereby permits myosin binding to approach an unperturbed binding equilibrium. In doing so, the muscle would then generate the full complement of isometric force appropriate to the stimulus. Perturbed myosin binding is the best theory available for understanding why airway narrowing is limited in the healthy lung and not in the asthmatic lung, but it is a very imperfect one. For example, it cannot explain the impressive effects of the history of muscle contraction and plasticity (5, 14), which are major determinants of muscle length, and it does not speak to the static length toward which the muscle would shorten in the event that myosin does come to an unperturbed binding equilibrium.
What other factors act to limit airway smooth muscle shortening? In this issue of the Journal of Applied Physiology, Meiss brings to our attention another idea (12). The shortening capacity of unloaded smooth muscle is enormous, being able to shorten to less than 30% of its optimal length. Airway smooth muscle is a syncytium comprised mostly of smooth muscle cells, aligned roughly along the axis of muscle shortening and held together by an intercellular connective tissue network. To conserve volume, as the muscle shortens it must also thicken; and as the muscle shortens and thickens, the intercellular connective tissue network must distort accordingly. In his article, Meiss suggests that at the extremes of muscle shortening it may be the radial expansion (relative to the axis of muscle shortening) of the intercellular connective tissue network that limits the ability of the muscle to shorten further. That is to say, the connective tissues ultimately impose a radial constraint that limits muscle shortening. This is called the radial constraint hypothesis.
In a series of meticulous experiments, Meiss first shows that artificial radial constraints, in the form of circumferential Silastic bands placed around isolated muscle strips, do in fact limit the ability of the muscle to shorten against small axial loads. In a second series of experiments, he demonstrates that digestion of the muscle strips with collagenase potentiates muscle shortening. Taken together, these experiments support the idea that radial constraints imposed on the muscle by its intercellular connective tissue lattice may well provide a mechanism that can act to limit muscle shortening not only in airway smooth muscle but also in other muscle systems that undergo extensive shortening.
This idea leads immediately to as series of unanswered issues and questions. The evidence provided thus far supports the notion that radial constraints can limit muscle shortening but falls short of establishing the degree to which radial constraints comprise an appreciable limiting mechanism for airway smooth muscle in situ, either in normal or pathological circumstances. Do the effects of radial constraints come to bear within the physiological range, i.e., before the axial load, or even airway closure, limits muscle shortening? How do the connective tissues comprising the radial constraint remodel with chronic airway inflammation, and what inflammatory mechanisms cause these changes?
Whereas we are only beginning to understand the potential role of radial constraints, this idea adds to our understanding of the mechanical loads against which the actomyosin molecular motor must shorten. Other extramuscular factors influencing this load include the elasticity of the airway wall, elastic tethering forces conferred by the surrounding lung parenchyma, active tethering forces conferred by contractile cells in the lung parenchyma, mechanical coupling of the airway to the parenchyma by the peribronchial adventitia, and buckling of the airway epithelium and submucosa (3, 15, 19). The radial constraint hypothesis now points to an additional factor, one internal to the muscle tissue but probably outside the muscle cell itself that can impede muscle shortening. And within the cell itself, still other factors come into play, including length-dependent activation (11), length-dependent rearrangements of the cytoskeleton and contractile machinery (5, 14), and length-dependent internal loads (18).
In addition, increasing evidence now suggests that cytokines such as
interleukin-1
and tumor necrosis factor-
augment responses to
bronchoconstrictor agonists (1) while attenuating the bronchodilation that can be effected by hormones and paracrine agents like epinephrine and PGE2 (16). Such cytokines,
along with growth factors and other inflammatory mediators, also result
in smooth muscle hyperplasia, at least in culture systems (9). In
culture, extracellular matrix proteins also influence the contractile
phenotype of airway smooth muscle cells (7). Whether asthmatic
inflammation can result in a hypercontractile phenotype remains to be
established. Inflammation, at least allergic inflammation, also appears
to result in an increased velocity of shortening of airway smooth muscle (13), perhaps caused by an increase in the expression of myosin
light chain kinase (8).
Each of these factors is not well understood. One of the major challenges for pulmonary and smooth muscle physiologists over the next several years will be to establish which of these factors comprise the essential determinants of airway narrowing, to determine how these factors are deranged in asthma, and to elucidate underlying mechanisms. Better understanding of these issues, taken together, may help us to appreciate why, in some patients, we observe excessive narrowing of the airway lumen caused by stimuli that would cause little or no narrowing in the normal individual. This is one of the cardinal features of asthma but it remains largely unexplained.
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