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For many years epithelial cells were considered to have the simple role of a barrier participating to mucous secretion and removal of noxious agents by their cilia. More recently these cells were found to have a much broader activity including the release of eicosanoids (7, 8), neural endopeptidases degrading neuropeptides (NEP) (9), fibronectin (8) participating to the regeneration of the normal epithelium, cytokines (10, 11) as well as they might have an immune function by their capability of antigen presentation (12).
1- Shedding of epithelial cells: In patients who died from an asthma attack, bronchial epithelium is mostly shed with separation of the mucosal cells leaving an intact basal cell layer. Some patients present a simple stratified non-ciliated epithelium with frequent mitoses that may represent a regeneration of the bronchial mucosa. Some patients have an increase in goblet cells.
Changes in the epithelium have been found almost constantly in living asthmatic patients but more often in moderately severe to severe patients than in mild asthmatics (13, 14). It is difficult to find a totally normal area of the bronchial epithelium as shown by low power transmission electron microscopy (3). Areas with desquamated epithelial cells where only basal cells are resting on the basement membrane are often seen (14). When the epithelial cells are present, the epithelium has a "fragile" appearance, the ciliated cells appearing swollen, vacuolized and often show loss of cilia (15). Separated columnar cells may appear normal and are still attached to each other at their luminal surface but they often undergo a necrosis (figure 1). Epithelial cells recovered by brushing are significantly less viable in asthmatics than in normal subjects (8). However both partial epithelial shedding and increase of goblet cells can be observed in normal non-smoking subjects due to artifacts of the biopsic procedure. The shedding of ciliated epithelial cells from basal cells may be due to eosinophil granule proteins (16), the release of TNF by macrophages, the release of proteases (17, 18) or oxygen free radicals by several cell types, or alternatively to the submucosal edema.
The consequences of epithelial shedding are likely to be or major importance in the pathogenesis of asthma. Nadel was the first to focus on the epithelial cell damage and suggested that asthma resulted from an epithelial injury that increases the freshold of re- flexes narrowing the airways. Degradation of neuropeptides such as VIP or substance P and kinins by endogenous NEP may be important but data in asthmatics are lacking to determine the exact role of these enzymes (9). Epithelial shedding (19) and epithelial damage characterized by an increase in intracellular space (20) have been correlated with bronchial hyperreactivity. The loss of the bronchial epithelium layer makes a denudation of nerves and mast cells as shown by electron microscopy (3). Moreover, it has been observed in vitro that epithelial cell removal increases the reactivity of smooth muscle to histamine or methacholine (21-23).
2- Patterns of activation of epithelium in asthma: Bronchial epithelial cells are activated in asthma as shown by the increased expression of membrane markers such as ICAM-1 or HLA-DR (24, 25), and, an increased spontaneous release of pro- inflammatory mediators (8).
The deleterious role of bronchial epithelium in asthma is unclear. It is likely that eicosanoids are involved. Increased levels of 15-lipoxygenase antigen were observed in the bronchial epithelial cells of asthmatic and bronchitic subjects compared with the same cell population in normal subjects and suggest that epithelial 15- lipoxygenase is induced by airway inflammatory disease (26). In asthma, epithelial cells obtained by bronchial brushing were shown to release a greater amount of 15-HETE spontaneously or after stimulation (8). 15-HETE is a biological mediator with the potential of influencing the inflammatory response. It is capable of stimulating the chemotaxis of inflammatory cells, inducing the release of mucus glycoprotein from human airways in culture, influencing 5-lipoxygenase activity in leukocytes and enhancing the early bronchoconstrictor response to inhaled allergen in atopic asthmatic subjects.
Endothelin-1 influences the airway caliber and it was showed that endothelin expression was found in the epithelium of the airways of asthmatics but not in normal subjects (27). This finding may explain partly the increased bronchial tone of the asthmatic airways.
3-Repair of epithelium: Regenerative changes are sometimes observed as demonstrated by varying stages of ciliogenesis in the non-ciliated "metaplastic" surface epithelium. Bronchial mucosal injury initiates a complex series of repair mechanisms (28), one of which is the reepithelialization of a denuded luminal surface but the regeneration of epithelium in asthma is usually normal by contradistinction to other bronchial inflammatory diseases such as chronic bronchitis. In asthma, epithelial cells have an increased expression of C-fos, a proto-oncogene regulating the transcription of many genes which plays a critical role in the cell cycle and differentiation (29). It is likely that bronchial epithelial cells initially affected by bronchial injury may be able to initiate repair of an injured area by producing chemotactic factors for epithelial cells.
Fibronectin is a large glycoprotein present in the extracellular matrix with a large number of binding sites for both cells and for other molecules. It is involved in epithelial cell adhesion and spreading and has been shown to increase epithelial cell regeneration suggesting an important role for fibronectin in the repair mechanisms of epithelial cell injury. Studies using bovine bronchi, have shown that these epithelial cells can release a chemotactic factor for airways epithelial cells and that this factor is likely to be fibronectin (30). Campbell et al have shown that epithelial cells of asthmatics obtained by brushing release more fibronectin than those of normal subjects (8) suggesting that bronchial epithelial cells, the cells that are affected by bronchial injury in asthma, are able to initiate repair of an injured area by producing a chemotactic factor for intact bronchial epithelial cells. However, many other cell types can release fibronectin in the bronchial mucosa and fibronectin is not the only substance mediating cell adhesion of epithelial cells as collagen and laminin exert similar effects through different receptors.
4-Activation of epithelial cells in asthma: Epithelial cells can be activated through different mechanisms. It has been recently observed that epithelial cells of asthmatics but not those of normal subjects bear the FceRI and FceRII receptors (Campbell, Chanez, Vignola and Bousquet, submitted) and that they can be directly activated by anti-IgE. It is therefore possible that cells can be directly triggered by allergens. Pollutants including NO2 and ozone can activate bronchial epithelial cells (31, 32). Finally, indirect mechanisms have been demonstrated. Finally, viruses can directly damage epithelial cells (33, 34). Histamine (35), platelet activating factor (36) or cytokines can activate bronchial epithelial cells. Other mediators such as cysteinyl leukotrienes have been shown to enhance growth of bronchial epithelial cells in vitro (37).
5- Inflammatory infiltrate within epithelium: Patients with an intact epithelium have an increased number of inflammatory cells among epithelial cells. These are constituted by granulated and degranulated eosinophils, lymphocytes, transitional forms of lymphocytes to plasma cells, activated macrophages and partly degranulated mast cells (3, 38, 39). In some severe asthmatic patients with a long course of the disease neutrophils were also found. These cells are target cells easily accessible to allergens or non-specific irritants.
6- Immunological role of epithelium: Epithelial cells bear class II antigens and two studies in normal individuals have suggested that they can present antigen to lymphocytes (12). In asthma, studies of cells obtained by brushing or by biopsies have shown that there is an increased expression of class II antigens but data is lacking to determine whether the presentation of antigen is enhanced.
7- Consequences of epithelial abnormalities: It has been shown that inhaled corticosteroids are able to repair bronchial epithelium. Biopsies have shown that there is an increased expression of class II antigens but data is lacking to determine whether the presentation of antigen is enhanced.
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