EDITORIAL FOCUS
Airway narrowing in asthma: does speed kill?

Harvard School of Public Health, Boston, Massachusetts 02115

	ARTICLE

TOP ARTICLE REFERENCES

THERE IS WIDESPREAD AGREEMENT that shortening of airway smooth muscle is the proximal cause of excessive airway narrowing during an asthma attack, with swelling of airway wall compartments and plugging by airway liquid or mucous being important amplifying factors (15, 18, 29). But it remains unclear why in asthma the muscle can shorten excessively.

The oldest and certainly the simplest explanation would be that muscle from the asthmatic airway is stronger than muscle from the healthy airway, but evidence in support of that hypothesis remains equivocal (2, 3, 24). Indeed, studies from the laboratory of Stephens and colleagues (1, 6, 11, 21) have emphasized that the force generation capacity of allergen-sensitized airway smooth muscle is no different from that of control muscle. As a result, the search for an explanation turned to other factors, and several alternative hypotheses have been advanced. These alternative hypotheses fall into three broad classes, each of which is consistent with remodeling events induced by the inflammatory microenvironment. These include changes of muscle mass (12, 26, 27), changes of the static load against which the muscle shortens (15, 28), and changes of the dynamic load that perturbs myosin binding (7, 9). Together, these hypotheses are attractive because they suggest a variety of mechanisms by which airway smooth muscle can shorten excessively even while the muscle itself remains essentially normal. As such, they have drawn attention away from the issue of the muscle and toward the issue of airway remodeling.

The report from Ma et al., one of the current articles in focus (Ref. 14, see p. L1181 in this issue), now draws attention back to the muscle itself. In a remarkable series of experiments, these investigators have characterized the contractility of airway smooth muscle cells obtained from bronchial biopsies of asthmatics and healthy volunteers. These studies show that cells from asthmatic subjects shorten faster and shorten more than do normal cells. Moreover, these investigators were able to associate these functional differences with increased content of message for myosin light chain kinase (MLCK).

What do we learn from these findings? First and most important, we learn that the airway smooth muscle cell from the asthmatic subject is not simply a "good" cell operating in a "bad" mechanical environment (7, 20). Instead, the cell itself is mechanically different. Second, we learn that these cellular changes would seem to have a relatively simple biochemical explanation. For technical reasons, expression of MLCK could not be measured directly, but the finding of increased content of message strongly implicates MLCK. Although regulation of myosin phosphorylation is a complex process with multiple kinase and phosphatase pathways, this finding substantially narrows the search for the culprit that may account for the mechanical changes observed in these cells. Third, these studies seem to rule out changes in the distribution of myosin heavy chain isoforms. Content and isoform distributions of message from asthmatic cells showed the presence of smooth muscle myosin heavy chain A (SM-A) but not SM-B, the latter of which contains a seven-amino acid insert, is typical of phasic rather than tonic smooth muscle, and is by far the faster of the two isoforms (13). Together, these findings confirm in muscle biopsy specimens from the asthmatic airway a number of findings from the allergen-sensitized dog model.

These new findings lead to new questions. First among these is why is the content of message for MLCK higher in muscle cells from asthmatic subjects? Second, how do these findings change our understanding of the mechanics of airway narrowing in asthma?

The authors are careful to point out that these studies pertain only to unloaded muscle and that the dynamics of shortening would be far different in cells loaded as they are in vivo. To account for increased shortening capacity of these unloaded cells, they point to the role of increased shortening velocity. They reason that upon activation virtually all muscle shortening is completed within the first few seconds. As such, the faster the muscle can shorten within this limited time window, the more it will shorten. Perhaps that is all there is to it, but perhaps not; in isotonic loading conditions at physiological levels of load, muscle shortening is indeed most rapid at the very beginning of the contraction, but appreciable shortening continues for at least 10 min after the onset of the contractile stimulus (9). An alternative idea for why intrinsically faster muscle might shorten more comes from consideration of the temporal fluctuations of the muscle load that are attributable to the action of spontaneous breathing (8, 9). Load fluctuations that are attendant to spontaneous breathing may be the most potent of all known bronchodilating agencies (10, 22). These load fluctuations perturb the binding of myosin to actin, causing myosin to detach from actin much sooner than it would have during an isometric contraction. But the faster the myosin cycling (i.e., the faster the muscle), the more difficult it is for imposed load fluctuations to perturb the actomyosin reaction. This is because the faster the intrinsic rate of cycling, the faster will a bridge, once becoming detached, reattach and contribute once again to active force and stiffness.

In many but not all species, smooth muscle in the developing lung has higher shortening velocity than in the mature lung (4, 19, 23, 25). Similarly, smooth muscle in the allergen-sensitized animal has higher shortening velocity than does muscle from control animals. If it is true that muscle that shortens faster also shortens more (5, 16), then the findings in the report of Ma et al. (14) may shed light on airway hyperresponsiveness and wheezing as they relate to lung maturation and allergen exposure. In that connection, does the atopic child get a double whammy? As regards the natural history of asthma (17), the findings in this report open such interesting possibilities.

	FOOTNOTES

Address for reprint requests and other correspondence: J. J. Fredberg, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (E-mail: jfredber{at}hsph.harvard.edu).

10.1152/ajplung.00190.2002

	REFERENCES

TOP ARTICLE REFERENCES

1.   Antonissen, LA, Mitchell RW, Kroeger EA, Krepon W, Tse KS, and Stephens NL. Mechanical alterations of airway smooth muscle in a canine asthmatic model. J Appl Physiol 46: 681-687, 1979.

2.   Black, J. Role of airway smooth muscle. Am J Respir Crit Care Med 153: S2-S4, 1996.

3.   Black, JL, and Johnson PR. What determines asthma phenotype? Is it the interaction between allergy and the smooth muscle? Am J Respir Crit Care Med 161: S207-S210, 2000.

4.   Chitano, P, Wang J, Cox CM, Stephens NL, and Murphy TM. Different ontogeny of rate of force generation and shortening velocity in guinea pig trachealis. J Appl Physiol 88: 1338-1345, 2000.

5.   Duguet, A, Biyah K, Minshall E, Gomes R, Wang CG, Taoudi-Benchekroun M, Bates JH, and Eidelman DH. Bronchial responsiveness among inbred mouse strains. Role of airway smooth-muscle shortening velocity. Am J Respir Crit Care Med 161: 839-848, 2000.

6.   Fan, T, Yang M, Halayko A, Mohapatra SS, and Stephens NL. Airway responsiveness in two inbred strains of mouse disparate in IgE and IL-4 production. Am J Respir Cell Mol Biol 17: 156-163, 1997.

7.   Fredberg, JJ. Frozen objects: small airways, big breaths, and asthma. J Allergy Clin Immunol 106: 615-624, 2000.

8.   Fredberg, JJ, Inouye D, Miller B, Nathan M, Jafari S, Raboudi SH, Butler JP, and Shore SA. Airway smooth muscle, tidal stretches, and dynamically determined contractile states. Am J Respir Crit Care Med 156: 1752-1759, 1997.

9.   Fredberg, JJ, Inouye DS, Mijailovich SM, and Butler JP. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm. Am J Respir Crit Care Med 159: 1-9, 1999.

10.   Gump, A, Haughney L, and Fredberg J. Relaxation of activated airway smooth muscle: relative potency of isoproterenol vs. tidal stretch. J Appl Physiol 90: 2306-2310, 2001.

11.   Jiang, H, Rao K, Halayko AJ, Liu X, and Stephens NL. Ragweed sensitization-induced increase of myosin light chain kinase content in canine airway smooth muscle. Am J Respir Cell Mol Biol 7: 567-573, 1992.

12.   Lambert, RK, Wiggs BR, Kuwano K, Hogg JC, and Pare PD. Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 74: 2771-2781, 1993.

13.   Lauzon, AM, Tyska MJ, Rovner AS, Freyzon Y, Warshaw DM, and Trybus KM. A 7-amino-acid insert in the heavy chain nucleotide binding loop alters the kinetics of smooth muscle myosin in the laser trap. J Muscle Res Cell Motil 19: 825-837, 1998.

14.   Ma, X, Cheng Z, Kong H, Wang Y, Unruh H, Stephens NL, and Laviolette M. Changes in biophysical and biochemical properties of single bronchial smooth muscle cells from asthmatic subjects. Am J Physiol Lung Cell Mol Physiol 283: L1181-L1189, 2002.

15.   Macklem, PT. A theoretical analysis of the effect of airway smooth muscle load on airway narrowing. Am J Respir Crit Care Med 153: 83-89, 1996.

16.   Martin, JG, Duguet A, and Eidelman DH. The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease. Eur Respir J 16: 349-354, 2000.

17.   Martinez, FD. Development of wheezing disorders and asthma in preschool children. Pediatrics 109: 362-367, 2002.

18.   Moreno, R, Hogg JC, and Paré PD. Mechanics of airway narrowing. Am Rev Respir Dis 133: 1171-1180, 1986.

19.   Murphy, TM, Mitchell RW, Halayko A, Roach J, Roy L, Kelly EA, Munoz NM, Stephens NL, and Leff AR. Effect of maturational changes in myosin content and morphometry on airway smooth muscle contraction. Am J Physiol Lung Cell Mol Physiol 260: L471-L480, 1991.

20.   Seow, CY, and Fredberg JJ. Historical perspective on airway smooth muscle: the saga of a frustrated cell. J Appl Physiol 91: 938-952, 2001.

21.   Seow, CY, and Stephens NL. Velocity-length-time relations in canine tracheal smooth muscle. J Appl Physiol 54: 2053-2057, 1988.

22.   Shen, X, Gunst SJ, and Tepper RS. Effect of tidal volume and frequency on airway responsiveness in mechanically ventilated rabbits. J Appl Physiol 83: 1202-1208, 1997.

23.   Shen, X, Bhargava V, Wodicka GR, Doerschuk CM, Gunst SJ, and Tepper RS. Greater airway narrowing in immature than mature rabbits during methacholine challenge. J Appl Physiol 81: 2637-2643, 1996.

24.   Solway, J, and Fredberg JJ. Perhaps airway smooth muscle dysfunction does contribute to bronchial hyperresponsiveness after all. Am J Respir Cell Mol Biol 17: 144-146, 1997.

25.   Tepper, R, Shen X, Bakan E, and Gunst SJ. Maximal airway responses in mature and immature rabbits during tidal ventilation. J Appl Physiol 79: 1190-1198, 1995.

26.   Thomson, RJ, Bramley AM, and Schellenberg RR. Airway muscle stereology: implications for increased shortening in asthma. Am J Respir Crit Care Med 154: 749-757, 1996.

27.   Wiggs, BR, Bosken C, Paré PD, James A, and Hogg JC. A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 145: 1251-1258, 1992.

28.   Wiggs, BR, Hrousis CA, Drazen JM, and Kamm RD. On the mechanism of mucosal folding in normal and asthmatic airways. J Appl Physiol 83: 1814-1821, 1997.

29.   Yager, D, Butler JP, Bastacky J, Israel E, Smith G, and Drazen JM. Amplification of airway constriction due to liquid filling of airway interstices. J Appl Physiol 66: 2873-2884, 1989.