Abstract
AM J RESPIR CRIT CARE MED 1999;160:S38−S43.The airway epithelium is a complex physicochemical barrier that plays a pivotal role in host defense. Epithelial cells have been shown to be a rich source of several classes of modulatory compounds, of which the cytokines form the largest group and possibly play the most important role in the etiology of airway disease. Evidence suggests that there are differences in the airway epithelial cells of individuals with and without respiratory disease, both with regard to (1) their capacity to express and release different types and quantities of specific cytokines and (2) their reactivity to inhaled irritants. Consequently, it is tempting to speculate that differences in epithelial cell function are an important determinant of the predisposition to respiratory disease. However, whether the differences are a result of an intrinsic defect, an acquired property due to the disease process itself, or a combination of the two, remains to be determined. In view of advances that have been made in the understanding of the putative underlying mechanisms in airway diseases, it should be possible to formulate novel therapeutic agents in the form of specific monoclonal antibodies directed against specific proinflammatory cytokines. Mills PR, Davies RJ, Devalia JL. Airway epithelial cells, cytokines, and pollutants.
The last decade has seen extensive research into the role of the bronchial epithelium in the pathogenesis of a number of pulmonary disease states. The entire respiratory tract is lined by epithelial cells, which, like those of the skin and gastrointestinal tract, are continually exposed to the external environment. The traditional view of the bronchial epithelium has been that it is a physical barrier to inhaled irritants and noxious substances, one with a mechanical function of propelling tracheobronchial secretions toward the pharynx. However, it is now clear that the bronchial epithelium, in addition to acting as a physicochemical barrier, plays a crucial role in initiating and augmenting pulmonary host defense mechanisms, both in health and in disease, by synthesizing and releasing a variety of mediators that can cause inflammatory cell differentiation, chemotaxis, and activation.
There are a number of distinct types of epithelial cells within the airways, of which columnar ciliated and goblet cells are the most prominent. Other subtypes include serous, basal, Clara, brush, and neuroendocrine cells. The different characteristics of these cells provide the bronchial epithelium as a whole with its complex functionality (1) (Figure 1). Ciliated cells are responsible for propelling the tracheobronchial secretions toward the pharynx and are also active in transepithelial electrolyte transport. Goblet and serous cells synthesize mucin and are responsible for the viscoelastic blanket of mucus that covers much of the bronchial epithelium. Basal cells contribute to the pseudostratified appearance of the epithelium and seem to be integrally involved in the attachment of superficial cells to the basement membrane. It has been suggested that these cells may also act as precursors to the other epithelial cell types within the airways. Clara cells become more plentiful in the distal airways and are thought to be active in the production of surfactant at these sites. The specific roles of the other epithelial cell types are less well characterized but are thought to be involved in cell-to-cell signaling processes.
Fig. 1. Diagram representing the multifunctional role of the airway epithelium in both health and disease.
[More] [Minimize]Several studies have demonstrated that bronchial epithelial cells synthesize and release a variety of different classes of proinflammatory mediators, including nitric oxide, endothelins, metabolites of arachidonic acid, and cytokines. Nitric oxide (NO) is synthesized from l-arginine by at least three different isoforms of nitric oxide synthase (NOS), of which two are constitutive and one is inducible. It has been suggested that the very small amounts (picomolar quantities) of NO synthesized endogenously by the constitutive isoforms of NOS are important in maintenance of physiological homeostasis. In contrast, it has been suggested that when NO is produced in excessive amounts (nanomolar quantities) by the inducible isoform of NOS, it leads to airway inflammation and epithelial damage (2). In addition, endothelins, peptides that are capable of causing profound vaso- and bronchoconstriction, are thought to be involved in the development of airflow obstruction in both asthma and chronic obstructive pulmonary disease (henceforth referred to as COPD) (3). Similarly, mediators such as the cysteinyl leukotrienes, derived from metabolism of arachidonic acid, have been shown to be capable of causing smooth muscle contraction, effector cell chemoattraction, changes in vascular permeability, and excessive production of mucus (4).
The production of proinflammatory cytokines by the airway epithelium has been of particular interest in allergic conditions such as asthma and allergic rhinitis, and has been studied widely because these compounds influence the activity of inflammatory cells such as eosinophils, T lymphocytes, and mast cells, which are the characteristic infiltrating cells in these disorders (5, 6). More recently, interest has focused on the role of airway epithelial cell-derived proinflammatory cytokines in the pathogenesis of nonallergic airway conditions, such as chronic bronchitis and COPD. We and others have demonstrated that bronchial epithelial cells can generate a variety of cytokines, both constitutively and after stimulation with different agents (7-11): these agents can be divided into four groups according to their functions.
Chemotactic cytokines include lymphocyte chemoattractant factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and members of the chemokine superfamily; they primarily influence the migration of inflammatory cells to sites of injury and disruption. Members of the chemokine superfamily appear to be the most potent chemotactic cytokines and are further divided into α and β subgroups, according to the presence or absence of an amino acid between the first two of four conserved cysteines. Several studies have demonstrated that the α-chemokine interleukin 8 (IL-8), which on a molar basis is one of the most potent activators and chemoattractant mediators for neutrophils, is synthesized and released in great quantities from airway epithelial cells (9, 10, 12). In view of its predominant effects on neutrophil cell biology, IL-8 has been of particular interest in studies investigating the pathogenesis of chronic bronchitis and COPD (13). Studies from our laboratory have demonstrated that Haemophilus influenzae endotoxin (HIE) significantly increases the release of IL-8 from primary bronchial epithelial cell cultures and that treatment with erythromycin abrogates the HIE-induced release of IL-8 from these cells (9). Similarly, studies of conditioned medium collected from cells treated with HIE demonstrate that this significantly increases neutrophil chemotaxis and neutrophil adherence to cultured human endothelial cells, compared with conditioned medium collected from untreated epithelial cell cultures. The conditioned medium-induced neutrophil chemotaxis is significantly attenuated by treatment of the cultures with erythromycin (9) and treatment of the conditioned medium with neutralizing antibodies to IL-8 and GM-CSF (14). IL-8 has also been shown to be a chemoattractant for eosinophils, in the presence of other mediators such as GM-CSF, and therefore may also play a role in the pathophysiology of allergic airway diseases. More recently, we and others have shown that bronchial epithelial cells can also release the β-chemokines RANTES (regulated on activated, normal T cell expressed and secreted) and monocyte chemotactic protein 1 (MCP-1), which are potent eosinophil and monocyte/basophil chemoattractants, respectively (11, 15).
Colony-stimulating factors promote the differentiation and survival of the recruited inflammatory cells. The most prominent member of this group of cytokines is GM-CSF, which as well as being a chemoattractant for eosinophils and neutrophils also potentiates the differentiation and survival of these cells (16-18). This effect has been demonstrated in cultured epithelial cells and has been shown to be inhibited by antibodies to GM-CSF. Studies of patients with asthma have demonstrated that there is a correlation between epithelial expression of GM-CSF and the number of activated eosinophils infiltrating the airways of these individuals, thus suggesting a pivotal role for this proinflammatory, epithelial-derived cytokine in the pathophysiology of asthma (19).
The multifunctional cytokines synthesized and released by airway epithelial cells include interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 11 (IL-11), and tumor necrosis factor α (TNF-α). These have pleiotropic proinflammatory effects on a variety of target cells, are involved in activation of B lymphocytes and monocytes, and induce acute-phase protein synthesis (10, 14, 18, 20). Some studies have shown that IL-6 can influence the expression of cell adhesion molecules (21). Similarly, studies of IL-1β and TNF-α have suggested that these cytokines play an important role in eosinophilic and neutrophilic inflammation, since they can stimulate a number of different cell types to increase the expression, synthesis, and release of several cytokines and cell adhesion molecules, including IL-8, RANTES, intercellular cell adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin (14, 18, 20, 22), which influence the activity and function of eosinophils and neutrophils. Indeed, our studies have demonstrated that TNF-α stimulates a dose- and time-dependent release of RANTES and soluble (s) ICAM-1 from cultured human bronchial epithelial cells (23), and suggest this multifunctional cytokine may be central in the development of inflammation within the airways of individuals with respiratory disease.
Growth factors such as transforming growth factor β (TGF-β) have been shown to be synthesized and released by bronchial epithelial cells (24); they are important mediators in the regulation of cell growth, differentiation, signaling, and repair, as well as in the downregulation of local inflammatory events (20). TGF-β has also been associated with fibrotic change within the lung parenchyma in allergic conditions such as asthma and less well-characterized diseases such as pulmonary fibrosis (25). It is probable that airway inflammation combined with dysregulation of repair processes is responsible for these changes and may also be associated with the small airway disease and fibrotic changes seen in COPD.
The development of specific epithelial cell culture techniques has enabled investigators to examine differences that exist in the airways between health and disease states (26). Much of the initial work has been conducted on allergic airway disease, namely asthma and allergic rhinitis, which has confirmed the belief that the airway epithelium is of pivotal importance in the augmentation of the inflammatory state seen in these conditions (Figure 2).
Fig. 2. The effect of atmospheric pollutants and irritants on airway epithelial cell cytokine production and consequent inflammatory effector cell migration in asthma and allergic rhinitis. CS = cigarette smoke.
[More] [Minimize]Studies using primary cultures of human nasal epithelial cells from atopic individuals with and without rhinitis have shown that there are major differences with respect to the amounts of proinflammatory mediators that are released from these cells (27). In general, nasal epithelial cells from atopic individuals release significantly greater amounts of IL-8, TNF-α, and GM-CSF than do the cells of nonatopic, nonrhinitic individuals. However, when the atopic individuals are subdivided into atopic individuals and atopic, nonrhinitic individuals (patients with eczema), the cells of the former release significantly greater amounts of IL-1β and RANTES, in addition to IL-8, TNF-α, and GM-CSF, than do the cells of patients with eczema (27). The release of IL-1β and RANTES from the cells of nonatopic subjects and patients with eczema was not found to be significantly different; however, the release of RANTES from the nasal epithelial cells of the rhinitic individuals was generally found to be four- to fivefold greater than that from the nasal epithelial cells of the nonatopic subjects and patients with eczema. An important observation from these studies was that the nasal epithelial cells cultured from the rhinitic group during the pollen season released significantly greater quantities of RANTES, compared with the cells cultured from the same individuals outside the pollen season.
More recently, we have demonstrated that primary bronchial epithelial cells cultured from atopic asthmatic individuals and from nonatopic, nonasthmatic individuals are also different with respect to the amounts and types of proinflammatory mediators that they release (28). As was shown to be the case with nasal epithelial cells of patients with atopic rhinitis, the bronchial epithelial cells of patients with asthma release significantly greater quantities of IL-8, GM-CSF, RANTES, and sICAM-1, compared with the bronchial epithelial cells of nonatopic, nonasthmatic individuals. In marked contrast to the nasal epithelial cells of nonatopic, nonrhinitic individuals, however, the bronchial epithelial cells of nonatopic, nonasthmatic individuals did not constitutively release detectable levels of RANTES.
These studies add weight to the hypothesis that phenotypic differences in mediator synthesis and release from the airway epithelial cells are likely to be instrumental in the development of allergic airway conditions such as asthma and allergic rhinitis.
It is clear from both epidemiological and human exposure studies that a number of commonly encountered atmospheric pollutants can cause significant morbidity, associated with changes in both pulmonary function and biochemical and cellular characteristics of airway secretions (29, 30). Although the precise mechanisms and cell types involved in pollutant-mediated effects in the airways are not clear, in vitro studies have suggested that fibroblasts, B lymphocytes, alveolar macrophages, and epithelial cells may all be involved. Not surprisingly, airway epithelial cells have received the most attention in mechanistic studies of air pollution-induced airway disease and it is suggested that these cells are likely to play a fundamental role in the pathogenesis of airway disease. Various studies have demonstrated that exposure of nasal or bronchial epithelial cells to nitrogen dioxide (NO2), ozone (O3), and diesel exhaust particles (DEPs) results in significant synthesis and release of proinflammatory mediators, including eicosanoids, cytokines, and adhesion molecules.
Exposure of confluent cultures of human bronchial epithelial cells to NO2 at a concentration of 400–800 ppb leads to significant attenuation of ciliary activity, increased cell membrane damage, and increased permeability, as assessed by release of radiolabeled chromium and passage of 14C-labeled bovine serum albumin across the cultures, as compared with exposure to air (31). In addition, exposure to NO2 results in significant release of leukotriene C4 (LTC4) and a variety of cytokines, including IL-8, TNF-α, and GM-CSF from the cultures (10, 31). Similarly, exposure of these cells for 6 h to 0–500 ppb O3 induces significant release of IL-8, GM-CSF, TNF-α, and sICAM-1 at concentrations of 10–50 ppb O3, which are well below the WHO safety guidelines, and also leads to significant epithelial cell damage at concentrations above 100 ppb O3 (32). Furthermore, these studies demonstrate that the O3-induced release of GM-CSF, TNF-α, and sICAM-1 can be blocked by treatment of the cells with 10−5 M nedocromil sodium and release of IL-8 could be blocked by treatment with glutathione, a naturally occurring intracellular antioxidant. Studies of exposure of human airway epithelial cell cultures to DEPs have shown that these agents cause a dose- and time-dependent increase in IL-8 and GM-CSF, an effect that is abrogated by pretreatment with a protein synthesis inhibitor, suggesting de novo synthesis of these mediators in response to DEP exposure (33). Other studies have shown a DEP-induced increase in electrical resistance across epithelial cell cultures, an attenuation of the ciliary beat frequency,and an increase in IL-8, GM-CSF, and sICAM-1 release (28). The effect on mediator release was still observed when the cultures were exposed to filtered DEP solution, suggesting that the chemical composition of the DEPs and not just their fine particulate nature is important for the DEP effect. Exposure of epithelial cell lines to cigarette smoke has also shown a dose-dependent cytotoxicity (34), a decrease in cell migration and attachment (35), and an increase in epithelial cell permeability associated with a depletion of the antioxidant glutathione (36, 37). In addition, exposure of human bronchial epithelial cell cultures to cigarette smoke extract and mainstream cigarette smoke results in a significant increase in IL-8 release above baseline levels (38, 39).
Studies examining the effect of pollutant exposures on epithelial cells derived from well-characterized groups of individuals have shown differential effects of pollutants on the cultured cells. Studies of nasal epithelial cells cultured from tissues of patients with atopic rhinitis during the pollen season and from tissues of patients with atopic asthma have shown that these release significantly greater quantities of IL-8 and/or RANTES after exposure for 6 h to 400 ppb NO2 and 10–50 ppb O3, compared with cells of nonatopic individuals (40, 41). In addition, exposure to these pollutants significantly decreases electrical resistance of the epithelial cultures of individuals with atopic rhinitis/asthma, compared with the cultures of individuals with nonatopic nonrhinitis/asthma, suggesting that the cells of the individuals with atopic rhinitis/asthma are more susceptible to cell membrane-damaging effects of pollutants than are the cells of individuals with nonatopic nonrhinitis/ asthma (41). More recently, exposure to DEPs has also been shown to increase significantly the release of IL-8, GM-CSF, and sICAM-1 from bronchial epithelial cells of the individuals with atopic asthma, as compared with the cells of the individuals without atopic asthma (42). These data suggest collectively that the increased responsiveness of the airways of allergic individuals to the effects of air pollutants may be a consequence of the increased susceptibility and ability of their airway epithelial cells to release significantly increased amounts of specific proinflammatory mediators in response to interaction with inhaled irritants.
We have cultured human bronchial epithelial cells as primary explant cultures from bronchial biopsies taken from three matched groups: lifelong nonsmokers, smokers with normal pulmonary function, and patients with COPD; and investigated these for constitutive and DEP/cigarette smoke-induced cytokine release (Figure 3). There was no difference in constitutive release of IL-8 or TNF-α from the cells of nonsmokers and smokers with normal pulmonary function; however, constitutive release of both of these mediators was significantly lower from the cells of the patients with COPD, suggesting that some form of downregulation of inflammatory mediator release may be occurring from the epithelial cells of individuals with COPD (43). Exposure to DEPs induced a dose-dependent increase in IL-8 release from the cells of lifelong nonsmokers, an effect that was significantly attenuated in the cells of patients with COPD. In contrast, the epithelial cells of smokers with normal pulmonary function did not respond to increasing concentrations of DEPs and IL-8 release remained at constitutive levels (44). Similarly, a 20-min exposure to mainstream cigarette smoke resulted in significant increases in IL-8 and TNF-α from the epithelial cells of nonsmokers and patients with COPD, the magnitude of the latter being significant but not as great (Table 1). Conversely, IL-8 and TNF-α release from the epithelial cells of smokers with normal pulmonary function did not increase after exposure to cigarette smoke.
Fig. 3. Schematic diagram depicting the putative role of the bronchial epithelium in the development of cigarette smoke- and particulate-induced airway inflammation. A pronounced inflammatory response with an increase in IL-8 release and consequent neutrophil chemoattraction is seen in nonsmokers; however, if particulate assault continues, either the IL-8 response is completely downregulated (conferring protection against ongoing airway inflammation) or it is only partially downregulated (resulting in an ongoing inflammatory response, neutrophil recruitment, and production of further IL-8), hence perpetuating the cycle of events.
[More] [Minimize]| Volunteer Group* | Exposure | Median IL-8 Release ( pg/μg cellular protein)† | ||
|---|---|---|---|---|
| Nonsmokers | Air | 18.45 (9.88–21.78) | ||
| CS | 43.75 (33.38–54.65) | |||
| Smokers | Air | 18.4 (11.9–24.03) | ||
| CS | 20.4 (16.43–27.0) | |||
| COPD | Air | 10.9 (6.58–13.3) | ||
| CS | 15.35 (11.38–21.48) |
Taken together, these results suggest that inflammatory mediator release from the bronchial epithelial cells of smokers with normal pulmonary function may be downregulated as a protective mechanism against ongoing airway inflammation and the subsequent development of airflow obstruction. It may be that this abrogation of the inflammatory response to inhaled irritants is incomplete within the epithelium of individuals who develop COPD, leading to a chronic inflammatory state with associated airway remodeling and progressive lung function decline. What is clear, however, is that, as with asthma and rhinitis, there are significant differences in the way the epithelial cells of smokers with and without COPD, and lifelong nonsmokers, respond to irritants. This could explain, at least in part, why some smokers develop airflow obstruction and others do not.
Further studies that investigate the mechanisms of the differential response of epithelial cells to inhaled irritants in smokers with and without COPD are required. It is likely that differences in mediator release are the result of transcriptional regulation of their gene products, as has been suggested with asthma (45), and it is therefore necessary to quantify the mRNA for the different mediators, as well as to look at specific transcriptional regulators such as the transcription factor nuclear factor κB (NF-κB). What remains unclear is whether these phenotypic differences cause an individual to develop the disease state or whether they arise as a result of their disease. If the former is true then one would expect there to be two distinct populations, with regard to epithelial mediator release, in young smokers, which would correspond approximately to the ratio of 10–15% of smokers who develop COPD, those with higher levels of IL-8 and TNF-α release being more likely to go on to develop COPD if they continue to smoke.
The studies outlined in this article point strongly to the epithelium, and the mediators that it is capable of synthesizing and releasing, as being of pivotal importance in the initiation and augmentation of the inflammatory response within the lungs. It is our hypothesis that there are fundamental differences in release profiles of inflammatory mediators from the bronchial epithelial cells of individuals with a variety of pulmonary diseases, including COPD, as compared with those who are not affected. It is these differences in epithelial cell functionality that are responsible for the development and escalation of the inflammatory response within the airways. Further research into the role of bronchial epithelial cells in the pathogenesis of COPD is clearly necessary in order that the mechanisms of inflammation and subsequent development of fixed airway narrowing can be fully understood. It is only then that new approaches to the treatment of this major public health burden can be devised, both to halt the progressive decline in pulmonary function and eventually to reverse its occurrence.
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