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Several pathologic changes occur in the airway epithelium in asthma, but the relationship between these changes and the initiation and progression of asthma remains poorly understood. One possibility is that changes in the structure and function of the epithelium induced by environmental exposure in genetically susceptible subjects represent primary pivotal events that occur early in the pathogenesis of asthma. Alternatively, these epithelial changes may occur simply as a consequence of pivotal early events in other systems, such as immune deviation in childhood to a helper T cell type 2 (Th2) subtype of CD4+ cells. Epithelial desquamation in asthma represents a pathologic change that is frequently cited as important for the mechanisms of airway remodeling and airway hyperresponsiveness. Desquamation of the epithelium may not represent true pathology, however, but may instead be an artifact of tissue sampling and handling. Evidence is more firm for other pathologic changes in the epithelium. For example, goblet cell numbers are increased in asthma, leading to increases in stored mucins in the epithelium and in secreted mucins in sputum. The functional consequences of these changes include sputum production and airway narrowing, which lead to asthma exacerbations. Currently available data suggest that an important mechanism for goblet cell hyperplasia in asthma is the action of Th2 cytokines. Improved understanding of epithelial goblet cell abnormalities in asthma will hopefully lead to novel therapies for mucin hypersecretion, which is an important cause of morbidity and mortality.
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Keywords: asthma; desquamation; epithelium; goblet cell; mucin
Airway remodeling is a summary term that describes structural changes in the airway in asthma. The pathology includes changes throughout the airway wall, including the epithelium (1). Although the attention of most clinical studies has focused on deposition of collagen beneath the basal lamina, interest in the relevance of other structural changes is growing. Changes in the structure of the epithelial cell compartment are of particular importance because these changes could lead to alterations in host defense and in the response of the epithelium to exogenous stimuli. This review focuses on epithelial desquamation and changes in goblet cell morphology and mucin gene expression in the airway in asthma.
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Desquamation of the airway epithelium has been considered a pathologic feature of asthma because of observations of epithelial desquamation in postmortem specimens (2, 3) and in endobronchial biopsies from patients with asthma (4, 5). The finding of clumps of epithelial cells in sputum from subjects with asthma ("Creola bodies") (6) and increased numbers of epithelial cells in bronchoalveolar lavage from subjects with asthma (7) has strengthened the idea that epithelial desquamation is a pathologic characteristic of asthma. Indeed, it has been hypothesized that airway hyperreactivity in asthma may be related to epithelial desquamation through mechanisms involving loss of epithelium-derived relaxing factor (10, 11). This hypothesis gained indirect support from clinical studies in subjects with asthma, which reported a significant inverse correlation between epithelial cell number in bronchoalveolar lavage and severity of airway hyperreactivity (5, 7, 8).
Despite the above findings, it is possible that epithelial
desquamation in asthma represents an artifact of tissue sampling
not a true pathologic feature of the disease. For example,
many studies of the cellular composition of bronchoalveolar lavage and sputum from healthy subjects and subjects with asthma
do not describe increased numbers of epithelial cells (12). In
addition, extensive epithelial desquamation has been found in examinations of bronchial biopsies from healthy volunteers (19).
This prompted the caution, "Mechanical damage of the bronchial
biopsies caused by the forceps should be considered before alterations in the epithelium are attributed to pulmonary disease"
(19). Indeed, some analyses of biopsies from healthy subjects and
subjects with asthma have documented epithelial desquamation in healthy subjects that is similar to that in subjects with
asthma (20, 21). Furthermore, although postmortem studies from
the early and mid-1900s describe epithelial cells mixed with mucus in the airway lumen (2, 22), a more recent postmortem study
of airways from subjects with asthma quantified epithelial desquamation and did not find it increased (23). Specifically, normal,
damaged, or desquamated epithelium was documented and quantified in nonasthmatic subjects dying from nonrespiratory disease;
the extent of these changes in the nonasthmatic subjects was similar to that observed in asthmatic subjects dying with or without
an asthma exacerbation (23).
Because of ongoing uncertainty about whether epithelial desquamation represents a pathologic feature of asthma or an artifact of tissue sampling and processing, we performed a detailed analysis of epithelial integrity in bronchial biopsies from healthy subjects and subjects with asthma (24). We found two distinct patterns of epithelial damage in bronchial biopsies from 14 subjects with asthma and 12 healthy control subjects. The most common appearance was of the basement membrane covered by a single layer of basal cells with no intact ciliated cells or goblet cells. Less commonly observed was complete denudation of the epithelial cells, including basal cells. We found that these epithelial changes were equally common in both groups (Figure 1). A single layer of basal cells covered approximately 50% of the basement membrane in both healthy subjects and subjects with asthma; an additional 10- 15% of the basement membrane was completely denuded of any epithelial cells. There was no correlation between the percent-predicted FEV1 and markers of epithelial desquamation in the asthmatic subgroup.
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The observation that the majority of the basement membrane in bronchial biopsy samples is covered by a single layer of basal cells shows that desmosomal connections of columnar cells to basal cells are more easily disrupted than the attachment of basal cells to the basement membrane. The attachment of columnar epithelial cells to basal cells in the airway epithelium depends mainly on desmosomal connections between columnar epithelial cells and basal cells (25). Basal cells are themselves anchored to the lamina densa of the basement membrane by hemidesmosomal connections and by other adhesive mechanisms involving integrins and anchoring filaments (26).
Airway eosinophilia is a characteristic feature of asthma, and it has been speculated that desquamation of epithelial cells may be due to the action of eosinophil granule proteins (4, 5, 27). However, epithelial desquamation is not reported in murine models of allergic inflammation, despite intense airway mucosal eosinophilia (28, 29). In addition, in subjects with asthma, we have found that allergen challenge does not cause any increase in measures of epithelial integrity, despite large increases in airway eosinophil numbers (30).
Taken together, these data argue that the epithelial desquamation observed in endobronchial biopsies from subjects with asthma is an artifact of tissue collection, fixation, and embedding. This conclusion does not rule out the possibility of weaker than normal connections of epithelial cells to basal cells or epithelial cells to basement membrane in asthma. Such pathology would explain higher than normal epithelial cell numbers in bronchial lavage fluid from subjects with asthma, because the trauma of the lavage procedure reveals underlying epithelial fragility. However, although it is possible that epithelial desquamation may occur in some instances in vivo in asthma, it is not proven that epithelial desquamation is a chronic phenotypic characteristic of the pathology of asthma. Indeed, the hypothesis that loss of the epithelial cell barrier leads to airway hyperresponsiveness and airway narrowing in asthma is being replaced by new hypotheses centered on an intact epithelium playing a participatory role as a proinflammatory organ in airway remodeling (31). In addition, remodeling events in the epithelium other than desquamation, especially goblet cell hyperplasia, which leads to increased epithelial mucin stores, are being recognized and emphasized. These discoveries, together with scant evidence of epithelial desquamation in mouse models of asthma, have combined to weaken support for the idea that epithelial desquamation is an important cause of functional abnormalities in asthma.
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Goblet cells and submucosal gland cells are the sources of mucin glycoproteins ("mucins") in the airway. Mucins are the major constituents of airway mucus and the major determinants of its viscoelastic and adhesive properties (32, 33). These glycoproteins are important for host defense but represent an important cause of airway obstruction when secreted in excess. Fatal asthma, for example, is nearly always associated with airway occlusion from mucous plugs (2, 3, 22, 23). In addition, sputum production is a common symptom in asthma, especially during asthma exacerbations (34), and a history of sputum production is independently associated with an accelerated rate of decline in FEV1 (35).
The mechanisms governing hypersecretion of mucus in asthma are poorly understood. Because mucus is principally a mixture of mucin glycoproteins and plasma proteins, it is possible that abnormalities in goblet cells, submucosal gland cells, and vascular endothelial cells could independently or together result in excess airway mucus. Blood vessel number is increased in the submucosa in asthma (36), and many of the inflammatory mediators associated with asthma, including histamine and leukotrienes (37, 38), are known to promote vascular permeability. Thus, excessive plasma leakage from blood vessels in the submucosa could contribute to acute or chronic mucus hypersecretion in asthma.
We have previously found increased concentrations of mucin glycoproteins in induced sputum from subjects with asthma, and this indicates an abnormality in goblet cell or submucosal gland cell secretion in asthma. The relative contribution of goblet cells and submucosal gland cells to the mucin component of airway mucus in asthma is uncertain. Prominence of the submucosal glands is usually not mentioned in bronchial biopsy studies of mild and moderate asthma, but increased submucosal gland volume is described in fatal cases of asthma (23). Goblet cell hyperplasia is also a prominent feature of the airway epithelium in cases of fatal asthma (3, 39, 40), but it has been uncertain whether goblet cell hyperplasia is a feature of mild and moderate asthma. One study of bronchial biopsies from subjects with mild asthma found no increase in airway epithelial goblet cells (21), but this study may have underestimated goblet cell numbers because of reliance on hematoxylin and eosin staining of the epithelium and semiquantitative methodology to count goblet cells.
To further explore abnormalities in goblet cell function in mild and moderate asthma, we analyzed goblet cell size and number in subjects with mild and moderate asthma and examined relationships between stored and secreted mucins in the airway (41). Specifically, we applied methods of design-based stereology to analyze goblet cell size and number in epithelial tissue sections, and we measured mucin-like glycoproteins in induced sputum by immunoassay. Stereology provides quantitative three-dimensional information from two-dimensional observations of tissue and offers a valid approach and method for quantifying the different components of remodeling in the airway. "Design-based stereology" describes any measurement protocol that is designed to ensure that the sampled fields of tissue are representative of the whole tissue sample (42). We applied design-based stereology to biopsy analysis by using an integrated system that includes a microscope, automated microscope stage, video camera, and computer equipped with stereology software. This system allows systematic random sampling of preselected numbers of tissue fields (usually 30 from 6 biopsies). Point and line grids are superimposed on the selected fields to allow the operator to measure volume and surface area by point and intersection counting, respectively (43). The automated microscopy stage and the stereology software also make possible the measurement of cell number. Cell numbers measured by stereology represent true numeric densities and are preferable to the more commonly measured cell profiles, which are subject to a cell size bias (overestimation of larger cells, underestimation of smaller cells).
By applying stereologic methods to bronchial biopsies from healthy subjects and subjects with asthma, we found that goblet cell numbers were 2.5-fold higher than normal in the airway epithelium in asthma (Figure 2) (41). This resulted in a volume of stored mucin in the epithelial compartment that was approximately three times higher than normal (Figure 2). Surprisingly, we found an inverse rather than a direct relationship between stored mucin in the epithelium and secreted mucin in induced sputum. This finding may have at least two pathophysiologic implications. First, because even mild asthma was associated with increased mucin stores, mucin hypersecretion resulting from acute degranulation of goblet cells might be an important mechanism for asthma exacerbations in these patients. Second, the finding that mucin stores in moderate asthma were no higher than in mild asthma raises the possibility that moderate asthma is associated with ongoing goblet cell degranulation, which could contribute to the pathophysiology of chronic airway narrowing in these subjects. This possibility is supported by the higher levels of mucin in induced sputum in moderate asthma than in mild asthma (41).
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The mechanism by which goblet cells increase in number in asthma is uncertain. It is possible that goblet cell metaplasia occurs by conversion of nongranulated secretory cells to goblet cells (44, 45). This may occur in part because of activation of mucin gene expression. Twelve different mucin genes have been cloned (MUC1-MUC4, MUC5AC, MUC5B, MUC6- MUC9, MUC12) (32, 46), and most are expressed in the airway. The genes for MUC2, MUC5AC, MUC5B, and MUC6 are located on chromosome 11 and encode the major gel-forming secreted mucins. This is in contrast to the genes for MUC1, MUC3, MUC4, and MUC12, which encode nonsecreted transmembrane mucin molecules.
We have measured mucin gene expression for 9 of the 12 mucin genes in airway biopsies from 11 subjects with asthma and 8 healthy controls, using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (41). We found that the most frequently expressed mucin gene in the airway in both healthy subjects and subjects with asthma was MUC5AC (Figure 3). MUC5AC expression was approximately 60% higher than normal in the subjects with asthma. Although this increase was not statistically significant, it was consistent with increased immunohistochemical expression of MUC5AC in bronchial biopsies from the same subjects. We also found abnormalities in gene expression for three other mucin genes in the subjects with asthma. Specifically, the expression levels of MUC2 and MUC4 were significantly increased, whereas the expression of MUC5B was significantly decreased. These findings implicate MUC5AC as the principal airway mucin in both health and asthma and suggest that upregulation of MUC5AC may account for increased mucin stores in asthma. The differential expression of MUC2, MUC4, and MUC5B in asthma requires further study. MUC2 protein was not detectable immunohistochemically in the airway in our study but has been in others (46), and it has been speculated that small changes in the relative proportions of MUC2 and MUC5AC in airway secretions may have deleterious consequences for the physical properties of mucus (46).
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The role of mucin gene activation in the mechanism of goblet cell metaplasia (GCM) has begun to be explored in rodent
models of asthma and in vitro in airway epithelial cells. Airway allergen challenge in sensitized mice causes airway eosinophilia and GCM (47). Interestingly, eosinophils are not
required for allergen-induced GCM (50). Rather, the helper T
cell type 2 (Th2) subtype of the CD4+ T cell is the major effector cell mediating this effect. The evidence for this is compelling. Adoptive transfer of Th2 cells, but not Th1 cells, into the
lungs of naive mice causes GCM (51, 52). In addition, overexpression of Th2 cytokines in mice, including interleukin (IL)-4,
IL-5, IL-9, and IL-13, leads to GCM (53). Currently available data for the mechanism of cytokine-induced GCM are
difficult to interpret and reveal significant gaps in knowledge.
IL-9 is the only Th2 cytokine that has been found to increase
MUC5AC expression in airway epithelial cells in vitro (59).
This effect of IL-9 is surprising, because epithelial cells express the unique 
chain of the IL-9 receptor but do not seem
to express the common 
chain. In addition, STAT6 (signal transducer and activator of transcription 6) activation is necessary for allergen-induced GCM in mice (60), but receptor
signaling for IL-9 is not thought to involve STAT6 activation.
In contrast, receptor signaling for IL-4 and IL-13 does involve
STAT6 activation, but these cytokines do not induce MUC5AC
gene expression in airway epithelial cells in vitro (61, 62). These
data suggest that indirect mechanisms are responsible for the
upregulation of MUC5AC and GCM that results from IL-4
and IL-13 administration to the airway. One indirect mechanism might be IL-9 activity downstream of IL-4 and IL-13 activity (63), but this has not yet been demonstrated. Other indirect mechanisms might include activation of epithelial cell
lipoxgenases or epidermal growth factor (EGF) receptors. For
example, IL-4 and IL-13 strongly enhance 15 lipoxygenase
(15-LO) expression in cultured airway epithelial cells (62).
However, although there are data that 15-LO products may
function as mucin secretagogues (64), there is no evidence that
these products increase mucin gene expression (62). The data
indicating a role for EGF receptors in the mechanism of IL-13-mediated mucin gene expression is stronger. In experiments using selective EGF receptor (EGFR) tyrosine kinase
inhibitors, it was found that EGFR activation is necessary for
IL-13-induced MUC5AC expression in rat airways (45). The
effect of IL-13 in these experiments involves secretion of tumor necrosis factor (TNF-) by activated neutrophils. This mechanism may be relevant in human asthma, because EGFR
expression localizes to airway goblet cells (65). Thus, inhibition of EGFR signaling has been proposed as a novel strategy
to reduce goblet cell numbers in the airway (66).
The principal functional consequence of increased goblet
cell numbers is thought to be hypersecretion of mucin glycoproteins when goblet cells degranulate. The mechanisms of
goblet cell degranulation in vivo are separate from those of
goblet cell hyperplasia or metaplasia and are not well understood. Studies of mouse and guinea pig models of asthma
clearly show that allergen challenge causes goblet cell degranulation (48, 67, 68). Possible mediators of goblet cell degranulation in airway diseases characterized by allergic airway inflammation include 5-lipoxygenase derivatives of arachidonic
acid (48), neutrophil elastase (69), chymase (70), and eosinophil cationic protein (71). However, we have found that allergen challenge is not associated with goblet cell degranulation
in subjects with asthma (72). Although inconsistent with animal studies, this finding is consistent with clinical studies of
the effects of 
agonists, which suggest that the principal mechanism of early- and late-phase bronchoconstriction to allergen is contraction of airway smooth muscle (73) and not
hypersecretion of mucins. Our data do not rule out the possibility that allergen exposure might cause goblet cell degranulation in other clinical circumstances, such as when subjects
have a respiratory tract infection.
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Epithelial desquamation of the epithelium in asthma may not represent true pathology but may instead be an artifact of tissue sampling and handling. In contrast, goblet cell hyperplasia is established as a pathologic characteristic of mild, moderate, and severe asthma. Abnormalities in goblet cell number are accompanied by changes in stored and secreted mucin. The functional consequences of these changes in mucin stores and secretion can contribute to the pathophysiologic mechanisms for multiple clinical abnormalities, including sputum production, airway narrowing, and asthma exacerbation. The mechanisms of goblet cell hyperplasia and goblet cell degranulation in asthma remain poorly understood but deserve further investigation because of the importance of mucin hypersecretion as a cause of asthma morbidity and mortality.
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Footnotes |
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Correspondence and requests for reprints should be addressed to John V. Fahy, M.D., Box 0111, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143. E-mail: jfahy{at}itsa.ucsf.edu
(Received in original form June 15, 2001 and accepted in revised form September 11, 2001).
Acknowledgments:
Supported by RO1 HL61662 and P50 HL 56385 from the National Heart, Lung,
and Blood Institute.
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