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POINT-COUNTERPOINT COMMENTS
University of British Columbia
The following letters are in response to Point:Counterpoint "Airway smooth muscle is/is not useful" that appears in this issue.
To the Editor: There is no shortage of speculation on what physiological roles airway smooth muscle may or may not have, as articulated by Fredberg (2). The latest candidate role for the muscle was eloquently proposed by Mead (4). The proposal, however, shares the same problem as all others: lack of compelling supporting data. The argument over the roles (or the lack thereof) of airway smooth muscle is in the realm of philosophical discussion. This, however, does not mean it is not useful. This debate is an opportunity for scientists to discuss possible mechanisms without the rigid requirement for supporting data. I am always puzzled by the structural difference of airway and pulmonary artery of comparable sizes (3), the former has a much thicker submucosal layer. Could this difference stem from the fact that airways experience negative transmural pressure during exhalation (especially forced expiration) and run the risk of collapsing? Setting aside the scientific rigor, I would argue that contraction of airway smooth muscle serves to stiffen the cartilage-free airways. A possible mechanism for this to work is to have radial tethers connecting the muscle layer to the relatively indistensible basement membrane and that the lamina propria-submucosal layer (sandwiched between the muscle layer and the basement membrane) is relatively fluid and yet incompressible, as modeled by my colleagues and me (6). Although a mathematical model is no substitute for real data, it provides a plausible explanation for the observations made by Olsen et al. (5) and Brackel et al. (1).
REFERENCES
Johns Hopkins University
To the Editor: Dr. Mead is to be congratulated for coming up with yet another hypothetical use for airway smooth muscle (3). It is nice to know that retirement has not blunted in the slightest his vivid imagination. In my commentary (5), I had identified and rejected 10 fanciful mechanisms that appeared in published work, but it seems that we now have an 11th hypothesis. With respect to this compulsive need to ascribe function to airway smooth muscle, I think Dr. Mead may be suffering from the same malady that Macklin so elegantly expressed (4), when he marveled that, "Organized as it is, into a very complex system, this muscle would seem of the utmost functional importance—in fact quite indispensable in respiration" (emphasis added). Although this complex structure has led many to dream of functional mechanisms, the physiology unfortunately just does not support this anatomical ignis fatuus. This latest notion proposed by Dr. Mead that somehow smooth muscle can both sense and adjust the depths of the bilayer fluid linings is something that would be very difficult to prove even if it were correct. And while such a creative term as "nerve-activated generational bronchoconstriction" brings up all sorts of imaginative pathways, it by itself can't fabricate the fine control system that would be needed for such a mechanism to function physiologically. Finally, the fact that dogs have survived quite well for as long as 5 yr after having their airway smooth muscle seriously impaired with bronchial thermoplasty (2) and that humans have not shown any clinical problems for at least 2 yr after similar treatment (1), clearly puts the burden of proof on those who continue to postulate a functional role for airway smooth muscle.
REFERENCES
University of Vermont
To the Editor: As he has in the past, Jere Mead certainly came up with a novel take on a provocative topic (4), whereas it appears that Jeff Fredberg took a more shotgun approach to killing off his own pet tissue (1). The lack of an obvious role for smooth muscle is not a new observation—I clearly recall Whitey Thurlbeck making the same point long ago (
1985), but I couldn't find the reference. To weigh in on the subject, my own belief is that airway smooth muscle provides an important structural support role. This is based on the following observation. Years ago as a follow-on to study the nonadrenergic inhibitory (NAI or erroneously known by some as NANC) neural control of airway smooth muscle, we attempted to stimulate NAI by lung deflation (and many other means as well to no avail). In a normal anesthetized cat, we could remove 25 ml of air or more below FRC with negative airway pressure produced by a large syringe. However, following atropine treatment, and hence loss of airway smooth muscle tone, we barely got 5 ml out before total airway collapse occurred, permitting no more air to escape. Clearly this experiment shows the importance of tonically active smooth muscle to the maintenance of airway integrity. Lastly, the observation by Halayko and Stephens (1) that ASM also exhibits a secretatory phenotype suggests another but nonstructural role not considered by either Mead or Fredberg. But let's not get too hasty to solve this enigma of ASM anytime soon, otherwise we risk putting ourselves all out of business!
REFERENCES
John B. Pierce Laboratory
New Haven, Connecticut
To the Editor: Airway conductance varies with changes in lung elastic pressure, and airway smooth muscle seems to fine tune the airway conductance by changing airway wall tension to counteract the variations in outward pull of the surrounding lung tissues. Airway conductance can double after a bronchodilator or drop to half after a bronchoconstrictor (1). The facts remain the same, but the explanations keep changing.
REFERENCES
University of Texas Medical Branch
To the Editor: Dr. Fredberg (1) argues that airway smooth muscle (ASM) is vestigial, ontologically derived from foregut, and meriting an evolutionary appendix analogy, now with basically only bad actor qualities that deserve to be, well, "fired" from their positions in the lung. Indeed, bronchial thermoplasty might be viewed as a panacea for misbehaving ASM in asthma, but could also be an irrevocable treatment with potentially dire consequences regarding feedback and therapeutic control of airway caliber and clearance.
Because airway secretions are the bane of asthma, COPD, and lung transplantation, further consideration is necessary before dismissing our manly Harley riders. For example, it is diminished mucociliary clearance and absence of a cough reflex in transplanted, denervated lungs (2) that necessitates external percussive therapy to clear airway secretions, until the cough reflex returns, if it ever does (3). This lack of mucociliary activity occurs in association with airway hyperreactivity (5), suggesting a feedback system out of balance, supporting a critical role of ASM in airway clearance (6). Furthermore, Dr. Mead's assertion, that an asthma attack demonstrates pathological ASM contraction as "positive feedback on display," (6) is insightful, and in fact, may be why airway nitric oxide is elevated in asthmatics (4): to counterbalance and defend airway caliber against a runaway positive feedback ASM contractile mechanism, attempting to clear the airway of voluminous mucous secretions.
However, cooked meat cannot be uncooked; there are no therapies to replace ASM. The strong likelihood that ASM performs important, albeit, yet unknown, functions encourages us to better understand it, before hyfrecating it into oblivion.
REFERENCES
University of Pennsylvania
To the Editor: "To study the abnormal is the best way of understanding the normal" (from William James, 1842-1910). Investigators posit that airway smooth muscle (ASM) is simply the "appendix" of the lung (4). Following this reasoning, ASM becomes important only in the pathogenesis of diseases characterized by airway hyperresponsiveness. Although an intriguing hypothesis, there exist substantial inconsistencies with the conceptual model. Unlike the appendix, a vestigial organ, ASM is highly organized in a geodesic manner regulated by an exquisitely complex network of innervation. This complexity begs for a rationale more than simple vestigial function. Indeed, ASM plays a critical role in lung development (1). Dysfunction of ASM during embryogenesis renders the lung hypoplastic (3). Given this evidence, the tenet that ASM remains vestigial may be dismissive. Investigators suggesting that ASM is important only in disease base their opinions on the notion that ASM only regulates bronchomotor tone. ASM, however, represents a tissue that secretes a variety of immunomodulatory factors that may act in either a paracrine or autocrine manner that affects lung physiology (5). In vivo studies in humans clearly demonstrate that ASM expresses a panoply of important cytokines, chemokines, growth factors, and extracellular matrix proteins that modulate and orchestrate the function of epithelium, nerves, and immunocytes. Over the past 100 years, our knowledge and understanding of ASM function has grown impressively yet remains incomplete. With new molecular approaches and targeted therapy to eliminate ASM, investigators will finally understand the depth and breadth of ASM function. Arguably, the amusing "born-to-lose" concept of ASM described by Fredberg (2) should be revised to "born to surprise." As stated at the turn of the 20th century by William James, "To study the abnormal is the best way of understanding the normal."
REFERENCES
Johns Hopkins University
To the Editor: One of the principal reasons that Fredberg (1) gives in support of his view that airway smooth muscle is not useful is: "Certainly there is no known disease entity or appreciable physiological deficit that is associated with loss of airway smooth muscle contractility." A review of the literature shows that the statement is incorrect, for there is a condition of enlargement of the trachea and bronchi (tracheobronchomegaly) that has been considered due, at least in part, to a marked decrease of smooth muscle tissue: Mounier-Kuhn syndrome (6) with 134 citations in PubMed. The major symptoms are the result of inefficient mucus clearance. "On being the right size" (2) is a fundamental requirement of optimal biological function that arises from the control of appropriate growth and form (5). Mead (3) has presented a compelling argument that there must be a "right size" of the airways for optimal mucus clearance. Since the right size of the airways cannot be constant because of variations in lung inflation and mucus production, it is not unreasonable to think of the airway smooth muscle as the controller of the right size. Then the "wrong size" is not just being too small, but also being too large. There is absolutely no question that major lung pathophysiology is caused by the tracheobronchomegaly that is associated with the Mounier-Kuhn syndrome. There should be some concern that optimal airway structure may be compromised by the current attempt to destroy airway smooth muscle with thermoplasty (4).
REFERENCES
This article has been cited by other articles:
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  Y. Bosse, A. Sobieszek, P. D. Pare, and C. Y. Seow Length Adaptation of Airway Smooth Muscle Proceedings of the ATS, January 1, 2008; 5(1): 62 - 67. [Abstract] [Full Text] [PDF]
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