Airway Smooth Muscle in Asthma — Not Just More of the Same
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《新英格兰医药杂志》
Airway smooth-muscle mass is increased in patients with asthma. This increase in muscle mass is quite marked in lung sections from patients who have died of asthma, but bronchial-biopsy studies indicate that even persons with mild-to-moderate asthma have increased airway smooth-muscle mass. Both hypertrophy and hyperplasia appear to contribute to this increase, and it is possible that airway smooth-muscle hyperplasia in asthma stems from the inflammatory milieu surrounding the asthmatic muscle. There are numerous smooth-muscle growth factors present in the asthmatic airway. Indeed, in culture, serum or bronchoalveolar-lavage fluid from patients with asthma causes greater proliferation of human airway smooth-muscle cells than does serum or lavage fluid from normal subjects.
However, a recent study by Johnson et al.1 suggests an alternative explanation. These authors showed that airway smooth muscle obtained from asthmatic subjects and grown in culture proliferates faster in response to serum than does smooth muscle from normal subjects. The phenotype was maintained through multiple weeks in culture and many passages — long after any inflammatory mediators present in the tissue would have been washed away. Thus, the airway smooth muscle from asthmatic patients is intrinsically different from normal airway smooth muscle. The same group now reports in this issue of the Journal (Roth et al., pages 560–574) that glucocorticoids do not inhibit the proliferation of cultured airway smooth-muscle cells from patients with asthma as they do those from normal subjects. The authors also provide data indicating that a deficit in the expression of the transcription factor CCAAT/enhancer binding protein (C/EBP) accounts for both the increased proliferative capacity of asthmatic airway smooth muscle and the inability of glucocorticoids to inhibit proliferation. Furthermore, the deficit in C/EBP expression appears to be specific to the airway smooth muscle.
An abnormality of airway smooth muscle is also thought to be responsible for another characteristic of asthma — airway hyperresponsiveness, which is defined as excessive airway narrowing in response to nonspecific contractile agonists. The initial studies evaluating smooth-muscle contractility in asthma were performed with the use of surgically resected airways or material obtained at autopsy, and they yielded conflicting data: some studies showed an increase in force generation in the asthmatic airways, and an equal number of studies showed no change. The studies were conducted at a time when the prevailing theories indicated that smooth-muscle length (and therefore airway diameter) was the result of a static balance between the generation of force by smooth muscle and the load placed on the muscle. Assessing maximal force thus made sense.
Since that time, however, it has become apparent that the shortening of airway smooth muscle is dynamic and that even breathing and sighing can affect muscle length. Accordingly, it is not maximal force generation but rather the shortening velocity that most likely determines the shortening capacity of airway smooth muscle. Indeed, within the past few years, the availability of airway smooth muscle from endobronchial biopsies has made it possible to compare the shortening velocity and the shortening capacity in airway smooth muscle from normal and asthmatic subjects. Clear and significant increases in both velocity and capacity were observed in the specimens from patients with asthma. Moreover, at least two studies in which airway biopsy specimens were examined have demonstrated increases in the expression and activity of myosin light-chain–kinase messenger RNA in the airway smooth muscle of patients with asthma; such increases could account for the increased velocity of shortening. Since myosin light-chain kinase phosphorylates the regulatory light chain of myosin and regulates the rate of cross-bridge cycling, the biochemistry may explain the physiological findings.
It is conceivable that the same intrinsic difference between asthmatic and normal smooth muscle (see Figure) accounts for both the increases in proliferation and the altered contractility. For example, a paradigm similar to asthmatic and normal humans may be found in Fisher and Lewis rats, strains that have innate airway hyperresponsiveness and hyporesponsiveness, respectively. The airway smooth muscle from the Fisher rat is characterized by both increased velocity of shortening and increased proliferation. Could a deficit in C/EBP account for changes in myosin light-chain–kinase expression and consequent effects on shortening velocity? The transcriptional regulation of myosin light-chain kinase in airway smooth muscle has been largely unexplored, although there are C/EBP consensus-binding sequences in the 5' untranslated region of the human gene encoding this kinase.
Figure. Possible Factors Leading to Hyperproliferative and Hypercontractile Phenotype in Asthmatic Airway Smooth Muscle and Consequent Excessive Airway Narrowing.
The origin of the cells that make up the extra smooth-muscle mass in patients with asthma is still an open question. It is possible that these cells are simply the offspring of other smooth-muscle cells. However, myofibroblasts are also observed in the subepithelial layer of the airways of asthmatic patients after an allergen challenge. These cells have a phenotype that is intermediate between fibroblasts and smooth-muscle cells, contain actin filaments, are capable of contracting, and under certain circumstances can differentiate into cells with a smooth-muscle phenotype. A recent report indicates that the myofibroblasts that populate the airways of patients with asthma may derive from fibrocytes — circulating collagen-expressing cells of hematopoietic origin.2 If fibrocytes are the stem cells responsible for the extra smooth muscle observed in asthma, it would follow that these cells might well be intrinsically different from normal smooth-muscle cells. It would be interesting to determine whether fibrocytes also lack C/EBP.
In short, airway smooth muscle in asthma is intrinsically different from the smooth muscle in normal airways. The implications of this difference for the narrowing and responsiveness of airways remain to be established, but it is clear that we may have to rethink our current beliefs about smooth-muscle function in asthma in the light of these observations.
Source Information
From the Physiology Program, Harvard School of Public Health, Boston.
References
Johnson PR, Roth M, Tamm M, et al. Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med 2001;164:474-477.
Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003;171:380-389.(Stephanie A. Shore, Ph.D.)
However, a recent study by Johnson et al.1 suggests an alternative explanation. These authors showed that airway smooth muscle obtained from asthmatic subjects and grown in culture proliferates faster in response to serum than does smooth muscle from normal subjects. The phenotype was maintained through multiple weeks in culture and many passages — long after any inflammatory mediators present in the tissue would have been washed away. Thus, the airway smooth muscle from asthmatic patients is intrinsically different from normal airway smooth muscle. The same group now reports in this issue of the Journal (Roth et al., pages 560–574) that glucocorticoids do not inhibit the proliferation of cultured airway smooth-muscle cells from patients with asthma as they do those from normal subjects. The authors also provide data indicating that a deficit in the expression of the transcription factor CCAAT/enhancer binding protein (C/EBP) accounts for both the increased proliferative capacity of asthmatic airway smooth muscle and the inability of glucocorticoids to inhibit proliferation. Furthermore, the deficit in C/EBP expression appears to be specific to the airway smooth muscle.
An abnormality of airway smooth muscle is also thought to be responsible for another characteristic of asthma — airway hyperresponsiveness, which is defined as excessive airway narrowing in response to nonspecific contractile agonists. The initial studies evaluating smooth-muscle contractility in asthma were performed with the use of surgically resected airways or material obtained at autopsy, and they yielded conflicting data: some studies showed an increase in force generation in the asthmatic airways, and an equal number of studies showed no change. The studies were conducted at a time when the prevailing theories indicated that smooth-muscle length (and therefore airway diameter) was the result of a static balance between the generation of force by smooth muscle and the load placed on the muscle. Assessing maximal force thus made sense.
Since that time, however, it has become apparent that the shortening of airway smooth muscle is dynamic and that even breathing and sighing can affect muscle length. Accordingly, it is not maximal force generation but rather the shortening velocity that most likely determines the shortening capacity of airway smooth muscle. Indeed, within the past few years, the availability of airway smooth muscle from endobronchial biopsies has made it possible to compare the shortening velocity and the shortening capacity in airway smooth muscle from normal and asthmatic subjects. Clear and significant increases in both velocity and capacity were observed in the specimens from patients with asthma. Moreover, at least two studies in which airway biopsy specimens were examined have demonstrated increases in the expression and activity of myosin light-chain–kinase messenger RNA in the airway smooth muscle of patients with asthma; such increases could account for the increased velocity of shortening. Since myosin light-chain kinase phosphorylates the regulatory light chain of myosin and regulates the rate of cross-bridge cycling, the biochemistry may explain the physiological findings.
It is conceivable that the same intrinsic difference between asthmatic and normal smooth muscle (see Figure) accounts for both the increases in proliferation and the altered contractility. For example, a paradigm similar to asthmatic and normal humans may be found in Fisher and Lewis rats, strains that have innate airway hyperresponsiveness and hyporesponsiveness, respectively. The airway smooth muscle from the Fisher rat is characterized by both increased velocity of shortening and increased proliferation. Could a deficit in C/EBP account for changes in myosin light-chain–kinase expression and consequent effects on shortening velocity? The transcriptional regulation of myosin light-chain kinase in airway smooth muscle has been largely unexplored, although there are C/EBP consensus-binding sequences in the 5' untranslated region of the human gene encoding this kinase.
Figure. Possible Factors Leading to Hyperproliferative and Hypercontractile Phenotype in Asthmatic Airway Smooth Muscle and Consequent Excessive Airway Narrowing.
The origin of the cells that make up the extra smooth-muscle mass in patients with asthma is still an open question. It is possible that these cells are simply the offspring of other smooth-muscle cells. However, myofibroblasts are also observed in the subepithelial layer of the airways of asthmatic patients after an allergen challenge. These cells have a phenotype that is intermediate between fibroblasts and smooth-muscle cells, contain actin filaments, are capable of contracting, and under certain circumstances can differentiate into cells with a smooth-muscle phenotype. A recent report indicates that the myofibroblasts that populate the airways of patients with asthma may derive from fibrocytes — circulating collagen-expressing cells of hematopoietic origin.2 If fibrocytes are the stem cells responsible for the extra smooth muscle observed in asthma, it would follow that these cells might well be intrinsically different from normal smooth-muscle cells. It would be interesting to determine whether fibrocytes also lack C/EBP.
In short, airway smooth muscle in asthma is intrinsically different from the smooth muscle in normal airways. The implications of this difference for the narrowing and responsiveness of airways remain to be established, but it is clear that we may have to rethink our current beliefs about smooth-muscle function in asthma in the light of these observations.
Source Information
From the Physiology Program, Harvard School of Public Health, Boston.
References
Johnson PR, Roth M, Tamm M, et al. Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med 2001;164:474-477.
Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003;171:380-389.(Stephanie A. Shore, Ph.D.)