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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 367-372, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200501-082PP

Pulmonary Perspective

Asthma: Is It Due to an Abnormal Airway Smooth Muscle Cell?

Peter Borger, Michael Tamm, Judith L. Black and Michael Roth

Pulmonary Cell Research, Departments of Research and Pulmonology and Internal Medicine, University Hospital Basel, Basel, Switzerland; and Department of Pharmacology, and the Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia

Correspondence and requests for reprints should be addressed to Peter Borger, Ph.D., Pulmonary Cell Research Department of Research University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland. E-mail: pieter.borger{at}unibas.ch

ABSTRACT

Asthma is an airway disease highly prevalent in westernized countries and of unknown etiology. Often, asthma is associated with atopy, but not all atopic individuals have asthma. Some patients with asthma outgrow symptoms, whereas many others acquire asthma later in life. Still other patients suffer from asthma their entire life. How can we explain these different patterns? It may be that asthma should be regarded as the clinical manifestation of a group of diseases with similar pathology due to a common factor. In this Pulmonary Perspective, we propose that an aberrant phenotype of airway smooth muscle (ASM) cells could be sufficient to explain the pathology of asthma. We will argue an abnormal ASM cell is a prerequisite to the development of asthma. Our postulate is that inadequate levels of C/EBP{alpha}, a protein that is pivotal for the suppression of both inflammation and proliferation responses, confer on ASM cells an activated phenotype that is more susceptible to mitogenic and contractile stimuli.

Key Words: airway smooth muscle • asthma • C/EBP

Smooth muscle cells surround the airways from the trachea down to the alveolar ducts. Inhalation of chemical irritants, smoke, or dust, or activation of arterial chemoreceptors, as well as release of inflammatory mediators such as histamine, thromboxane, and leukotrienes, can induce constriction of the smooth muscle. In patients with asthma, the constriction caused by these and other (nonspecific) stimuli is exaggerated and abnormal. Many years of intense scrutiny have revealed that the airways of patients with asthma are characterized by infiltrates of mast cells, eosinophils, macrophages, and T lymphocytes. In addition, the asthmatic lung shows persistent airway wall remodeling. Despite this knowledge, we still cannot answer the pivotal question that drives asthma research: Why do the airways of patients with asthma constrict so forcefully in response to a wide range of stimuli? Airway inflammation might be an important factor that is linked to the severity of asthma attacks, but the airway inflammation does not have to be T-cell mediated per se. On the basis of our results in human airway smooth muscle (ASM) cells, we hypothesize that the lack of a crucial transcription factor, CCAAT/enhancer binding protein-{alpha} (C/EBP{alpha}), results from faulty translation of the respective mRNA, which in turn can be linked to most of the documented features of the pathology of asthma. Some of the results of these studies have been previously reported in the form of an abstract (1).

IS ASTHMA MERELY AN INFLAMMATORY DISEASE?

Two decades ago, Mosmann and colleagues reported that Th1 and Th2 cells determined the type of immune response in mice (2). Soon thereafter, it was established that Th2 cells in mice models produced granulocyte-macrophage colony–stimulating factor (GM-CSF), interleukin (IL)-3, IL-4, IL-5, IL-9, and IL-13, and hence regulated IgE synthesis as well as the production, recruitment, and activation of mast cells and eosinophils. Most of the relevant cytokines can also be produced by other cell types present in the lung, including ASM cells (Table 1).


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  		TABLE 1. CELLS AND THEIR MEDIATORS IN ASTHMA

 
The excess of Th2 cells and/or their soluble mediators potentially explained many inflammatory phenomena of (allergic) asthma in both animals and humans, including eosinophilia and atopy. Studies in humans showed that Th2 cells and their respective cytokines were more abundant in serum and bronchoalveolar lavage fluid of patients with (allergic) asthma compared with control subjects (3–6). These findings led to the general acceptance of the postulate that asthma involved chronic inflammation of the lung, probably the result of an increased Th2-like response, with high levels of IL-4, IL-5, and IL-13 (7).

There must, however, be more to asthma than Th2-cell–mediated inflammation. T cells contribute to inflammatory responses, but their role in asthma could be limited. T-cell numbers do not correlate with severity or persistence of asthma and are also not associated with exacerbations or diminished responsiveness to steroids. In this context, it is important to note that studies using cyclosporine to treat (severe) asthma raised questions about the role of T cells in the pathogenesis of asthma. Cyclosporine blocks T-cell activation and inhibits the release of inflammatory mediators, such as IL-2, IL-4, and IL-5 (8–10). The studies showed that cyclosporine blocked the late asthmatic reaction, but not the early asthmatic response (11, 12). Such findings suggest that the early asthmatic response is not T-cell mediated, but rather implicate direct effects of inflammatory mediators on ASM contraction that cannot be counteracted by blocking T-cell activity.

That asthma is not merely Th2 inflammation is also evident from additional clinical trials. Administration of anti–IL-5 monoclonal antibodies effectively reduced eosinophils in the airways and in peripheral blood in patients with asthma, but did not relieve asthma symptoms or bronchial hyperresponsiveness (13, 14). Recombinant soluble IL-4 receptor administration has been somewhat more successful, but still has not met the expectations of complete recovery from asthma symptoms (13). This shows that Th2 inflammation alone is insufficient to explain the hyperresponsiveness of the airways of patients with asthma. Therefore, it remains an open question as to why the airways of patients with asthma exhibit such abnormal behavior.

Is it really airway inflammation that underlies the abnormal responsiveness of the ASM cells, or could it be the other way around? Are the resident ASM cells of patients with asthma abnormal in their behavior and can they initiate an (Th2-like) inflammatory response? The ASM cell is a rich source of proinflammatory cytokines, chemokines, and growth factors (15, 16), and this fact alone indicates that the ASM cells may fulfill a more active role in inflammatory lung diseases than currently envisioned.

THE AIRWAYS IN ASTHMA

The histology of cross-sections of the airways of patients with asthma is distinctly different from that of healthy subjects. Epithelial goblet cell hypertrophy and hyperplasia, mucus plugs, subepithelial fibrosis, and increased vascularization of the airway wall are present. The most striking feature is the increased bulk of ASM cells (Figure 1). The increase in muscle mass is quite marked in patients who have died of asthma, but can also be found in bronchial biopsies taken from patients with mild or moderate asthma, and is believed to result from ongoing airway inflammation.


Figure 1
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  		Figure 1. Histology of a representative airway of an individual who died of causes unrelated to asthma (left panel), a patient with mild-to-moderate asthma (middle panel), and a patient with asthma who died of status asthmaticus (right panel). The asthmatic airway demonstrates the distinct thickening of the basement membrane (1), and the increase of the bulk of smooth muscle cells surrounding the airway (2).

 
Numerous growth factors and cytokines that regulate the activity and proliferation of ASM cells are found in asthmatic airways. Bronchoalveolar lavage fluid of patients with asthma was found to increase proliferation of normal human ASM cells, an effect that was further augmented after allergen challenge, suggesting a direct activating effect of allergens on ASM cells (17). Recently, it was demonstrated that Der p 1, a major house dust mite allergen, activated the ERK1/2 signaling cascade in ASM cells, showing that allergens may indeed have a direct proasthmatic effect on ASM cells (18). In addition, we observed that incubation of normal human ASM cells with allergic serum and subsequent exposure to allergen resulted in an increased proliferation and enhanced expression of c-fos and c-jun, the two components that form the activator protein 1 (AP-1) transcription factor that is associated with cell proliferation (unpublished observations). Normal ASM cells may also become more responsive to activation- and/or growth-promoting cytokines because the expression of cytokine receptors is increased after exposure to atopic asthmatic serum (19). Considering the mitogenic and priming nature of the mediators released by inflamed tissue, it is not too surprising that they can induce ASM cell proliferation and thus may contribute to ASM cell hyperplasia. However, the cellular source of these inflammatory mediators is largely a matter of speculation. Based mainly on the Th2 paradigm, several cell types have been suggested, including Th2 cells, eosinophils, mast cells, and epithelial cells (Table 1). We argue that the biology of ASM cells suggests that this cell may be the key player in the pathogenesis of asthma, explaining both inflammation and remodeling.

THE ABNORMAL ASM CELLS OF PATIENTS WITH ASTHMA

Because ASM cells are directly responsible for airway constriction, it is reasonable to propose that an ASM cell abnormality could underlie the airway hyperresponsiveness of patients with asthma (20). It has been difficult to assess ASM cell function in asthma because it was believed to be too risky to obtain these cells from patients with asthma for culture in the laboratory. Recently, through the willingness to do bronchoscopy and biopsy in asthmatic volunteers, it has become possible to compare ASM cells of healthy control subjects with that of patients with asthma. Our group was the first to provide evidence for an intrinsic abnormality of ASM cells obtained from patients with asthma. In 2001, we reported that ASM cells from patients with asthma proliferate significantly faster than cells from control subjects as assessed by manual cell counts, [3H]-thymidine incorporation, and fluorescence-activated cell sorting analysis of their DNA content (21). This increased in vitro proliferation rate may be responsible in vivo for the increase in ASM mass in the airways of patients with asthma (22). A recent report showed that hyperthermal removal of the ASM bundles significantly reduced asthma symptoms and improved lung function (23). It remains to be established, however, whether removal of ASM bundles reduces airway inflammation as well.

There are more differences between ASM cells of healthy subjects and subjects with asthma, however. In response to transforming growth factor (TGF)-beta, ASM cells of patients with asthma produce more connective tissue growth factor (CTGF), an important contributor to the increased deposition of extracellular matrix (24). Cultured ASM cells of patients with asthma produce less prostaglandin E2 (PGE2) as a result of lower COX2 expression (25), but, probably as a compensatory mechanism, these cells are more sensitive to PGE2 due to increased numbers of E-prostanoid receptors (26). PGE2 directly counteracts airway constriction (27, 28). Reduced levels of PGE2 could thus result in less airway relaxation, or lower the threshold for other substances that initiate ASM cell contraction. Finally, our group showed that relative to control subjects, ASM cells of patients with asthma released more IL-6 on stimulation with recombinant OX40, a molecule present on activated T cells, indicating an interaction between these cells in the airways of patients with asthma (29). Together, these observations suggest that ASM cells from patients with asthma have an activated phenotype that may be attributed to an intrinsic (or acquired) abnormality. The question is now whether a single factor could account for all these abnormalities of the asthmatic ASM cell. If such a factor exists, it must have a broad range of action.

IS C/EBP{alpha} THE ASTHMA PROTEIN?

C/EBP{alpha} is an important regulator of cell proliferation and inflammation. It has several domains that bind to and influence the action of several transcription factors and cyclin-dependent kinases, and it has a domain for DNA binding (30, 31). C/EBP{alpha} is expressed as two isoforms, p30 and p42, which are regulated at the post-transcriptional level through alternative translation initiation sites present in the messenger RNA (30). In human smooth muscle cells and fibroblasts, C/EBP{alpha} determines the rate of proliferation through induction of the cell cycle inhibitor p21waf1/cip1 (32–34). In normal ASM cells, steroids and beta-mimetics also exert their inhibitory effects via C/EBP{alpha} in a complex with the glucocorticoid receptor (GR) that activates the p21waf1/cip1 gene (33). A combination of steroids and beta-mimetics induces an even faster and persistent activation of the C/EBP{alpha}–GR complex and p21waf1/cip1 (33). Apparently, cell cycle repression by these drugs requires the simultaneous activation of both the GR and C/EBP{alpha}.

We have recently reported that ASM cells of patients with asthma lack the antiproliferative isoform of C/EBP{alpha}, and, because the complex with the GR cannot be formed, the p21waf1/cip1 gene cannot be sufficiently induced (35). The consequence is that steroids are unable to block the proliferation of ASM cells of patients with asthma. Restoration of C/EBP{alpha} protein expression in ASM cells of patients with asthma through introduction of an expression vector rendered the cells susceptible to the inhibitory action of steroids (35). Absence of C/EBP{alpha} protein could potentially explain the increased in vitro proliferation rate of ASM cells obtained from patients with asthma and may underlie ASM hyperplasia in vivo. In addition, absence of the C/EBP{alpha} protein may explain airway inflammation and hyperresponsiveness.

C/EBP{alpha} AND AIRWAY INFLAMMATION

Nuclear factor (NF)-{kappa}B is an important transcription factor required to induce an inflammatory response through the activation of proinflammatory genes leading to the increased synthesis of cytokines, adhesion molecules, chemokines, and growth factors (36, 37). C/EBP{alpha} has the potential to silence this inflammatory response through interference with NF-{kappa}B–driven gene expression (38, 39). Considering these interactions, it is not surprising that NF-{kappa}B has been implicated in asthma-associated inflammation (40, 41). ASM cells have the capacity to produce many cytokines that are believed to be important in asthma, including IL-1, IL-2, IL-5, IL-6, IL-11, and IL-12 (8, 9). ASM cells also produce thymus and activation–regulated chemokine (TARC) (36). TARC selectively induces the migration of Th2 cells and is up-regulated in the airways of patients with asthma (37). The expression of these cytokines (31) and TARC (37) critically depends on NF-{kappa}B or C/EBP binding sites in their promoters. These data suggest that the ASM cell itself is able to generate an (Th2-like) inflammatory environment in the airways through excess secretion of inflammatory mediators and increased migration of inflammatory cells. Because C/EBP{alpha} is mainly a negative regulator of gene expression, diminished expression of C/EBP{alpha} in ASM cells of patients with asthma may initiate the airway inflammation through the release of proinflammatory mediators into the airway. Once the inflammation has started, it may perpetuate itself and become chronic. Eosinophils, mast cells, T cells, and macrophages have all been implicated in asthma and are present in the asthmatic lung to sustain the inflammatory environment through the release of cytokines, such as IL-1beta, IL-4, IL-5, and tumor necrosis factor (TNF). It is of particular interest that IL-4 has the ability to inhibit C/EBP{alpha} (42), and might thus further sustain airway inflammation initiated by the ASM cell. The airway epithelium may be another important source of cytokines that further aggravate pathologic ASM cell behavior. For example, after exposure to protease activity of allergens, epithelial cells start to produce and release a plethora of ASM cell–activating mediators (43–45).

The observation that ASM cells of patients with asthma produce less PGE2 than those of normal subjects suggests that PGE2 may also be important for sustaining a Th2-like inflammation. PGE2 is a potent inhibitor of proliferation and activity of many cell types. Binding of PGE2 to its receptor generates cyclic AMP (cAMP) inside the cell, which counteracts the production of many proinflammatory cytokines and chemokines. Th2-like cytokines, in particular IL-4 and IL-5, are less susceptible to the inhibitory effect of cAMP than Th1-like cytokines (12, 46, 47). Lower levels of PGE2 produced by ASM cells of individuals with asthma may thus be insufficient to block the production of Th2-like cytokines and could explain the increased presence of Th2-like lymphocytes in the asthmatic lung. Intriguingly, expression of COX2, the crucial gene in PGE2 production, critically depends on C/EBPs (48).

C/EBP{alpha} AND AIRWAY HYPERRESPONSIVENESS

An increase in the contractile properties of the airways is likely a major component of asthma pathology, but this has been difficult to study. The availability of endobronchial biopsies of patients with asthma also provided an opportunity to compare the shortening velocity and the shortening capacity of ASM cells from normal subjects and subjects with asthma. Significant increases in both contractile parameters have been found in airway biopsy specimens of patients with asthma (49, 50). These studies reported that single ASM cells demonstrated increased intrinsic contractile properties, which coincided with enhanced expression levels of myosin light-chain kinase (MLCK) messenger RNA in ASM cells of patients with asthma (50). Such increases might account for the increased velocity of shortening, since MLCK phosphorylates the regulatory light chain of myosin and regulates the rate of cross-bridge cycling, and therefore the contractile properties of ASM cells. The promoter that regulates the expression of this kinase contains several C/EBP binding sites (51). It is therefore conceivable that a deficit in C/EBP{alpha} expression might also account for the observed increased expression of MLCK in ASM cells of patients with asthma and hence for an increased shortening velocity of ASM cells when exposed to contractile stimuli (50). If airway constriction depends on the shortening velocity of ASM cells, which is increased in patients with asthma, it may still explain the beneficial actions of steroids in the treatment of asthma. Although steroids did not affect proliferation, this class of drugs inhibited the production of IL-6 in ASM cells of both healthy subjects and subjects with asthma (35). This shows that steroids counteract the ASM cell–initiated inflammation, but do not affect ASM proliferation.

However, these findings still do not fully explain the nexus between ASM-cell behavior and asthma. To induce airway constriction, an appropriate trigger is required as well. For the asthmatic ASM cell, such triggers could be several, and might originate from neuronal (e.g., neurokinin A, acetylcholine), mast cell–derived (e.g., histamine, leukotrienes), or other cellular sources (eosinophils, epithelium). For instance, mast cell–derived histamine may cause airway constriction in an atopic (Th2-like) background, whereas mediators such as acetylcholine, neurokinin A, and leukotrienes may cause a similar airway hyperresponsiveness in a nonatopic environment. In an IL-1beta–dominated inflammatory milieu that protects from the "classic" reaction (52), the triggers for ASM cell contraction might be of different character—for instance, neuronal. Indeed, it has been demonstrated that IL-1beta and TNF-{alpha} enhanced ASM contractility in response to acetylcholine or neurokinin A (53). An increased MLCK activity in asthmatic ASM cells together with the knowledge that several distinct triggers can activate an exaggerated contraction of the asthmatic ASM cell may provide a basis for understanding nonspecific airway hyperresponsiveness and asthma heterogeneity.

DISCUSSION AND FUTURE DIRECTIONS

The goal of this perspective is to encourage scientists and physicians to reconsider the role of the ASM cell in the pathogenesis of asthma. We propose that the ASM cell could be the most important cell type in asthma pathology. Not only does the ASM cell cause the airways to constrict but ASM cells of patients with asthma also proliferate faster, produce more cytokines and growth factors, and contract to a greater degree. In this perspective, we have summarized the evidence that the ASM cell has the ability to induce and sustain an environment that promotes airway inflammation and remodeling. We have also argued that the absence of the full-length C/EBP{alpha} protein, which is a feature of ASM cells of patients with asthma, potentially explains most of the pathologic and clinical features of asthma, including inflammation, remodeling, and airway hyperresponsiveness. At present, it is not known why the ASM cells of patients with asthma have reduced levels of C/EBP{alpha}, but our observations strongly suggest that it is not due to a diminished transcription of the CEBPA gene. Rather, the translation of the messenger RNA into the full-length protein seems to be disturbed (1). In addition, our most recent studies identified the lack of the C/EBP{alpha} protein as specific for ASM cells of patients with asthma, whereas patients with chronic obstructive pulmonary disease and emphysema expressed normal levels. The presence or absence of C/EBP{alpha} in ASM cells may therefore also become helpful in distinguishing between asthma and chronic obstructive pulmonary disease at an early stage of the disease (Table 2).


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  		TABLE 2. HOW TO DEMARCATE HEALTHY SUBJECTS, PATIENTS WITH ASTHMA, AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE BASED ON THE EXPRESSION OF C/EBP{alpha} IN AIRWAY SMOOTH MUSCLE CELLS

 
There are many questions that still have to be addressed, for example, as follows: (1) could asthma be the result of the existence of a less differentiated premature type of ASM cell, a problem that could be rectified when the full-length C/EBP{alpha} can be reestablished; (2) is the abnormal ASM cell of patients with asthma based on a genetic abnormality that affects the translation of the full-length C/EBP{alpha} protein; and (3) can chronic inflammation or viral infection irreversibly inhibit the translation of C/EBP{alpha} mRNA and induce an asthma-like phenotype? Answering these questions will lead to a more complete understanding of the still elusive pathogenesis of asthma. The central role we propose for the ASM cell in asthma pathology is presented in Figure 2.


Figure 2
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  		Figure 2. Flow diagram demonstrating the proposed central role of the airway smooth muscle (ASM) cell in airway inflammation, remodeling, and constriction. Due to predisposition or environmental stress, ASM cells of patients with asthma do not express appropriate levels of the CCAAT/enhancer binding protein-{alpha} (C/EBP{alpha}), an important inhibitor of cell cycle progression and transcription of proinflammatory genes. Lack of C/EBP{alpha} renders the ASM cell a phenotype that proliferates faster, produces more proinflammatory mediators, and constricts more readily in response to contractile stimuli due to increased levels of myosin light-chain kinase (MLCK).

 
FOOTNOTES

Originally Published in Press as DOI: 10.1164/rccm.200501-082PP on May 11, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form January 19, 2005; accepted in final form May 10, 2006

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