Bronchial epithelium: morphology, function and pathophysiology in asthma.

ARTICLE

MORPHOLOGY OF THE BRONCHIAL EPITHELIUM

The bronchial epithelium forms the interface between the respiratory system and the inspired air. The epithelial layer rests upon a connective tissue substratum consisting of a basement membrane, lamina propria and submucosa, containing smooth muscle, glands and cartilage [1]. The bronchial epithelium is composed of three main cell types, which together form a pseudo-
stratified ciliated layer.

Ciliated cells are terminally differentiated columnar cells that are thought to originate from basal or secretory cells [2, 3]. Their main function is to remove particulate matter by means of the mucociliary stairway.

Secretory cells, which comprise 15-25% of the bronchial epithelium, are present in several forms. Mucous or goblet cells are the main producers of airway mucus, in which inhaled particles, including viruses and bacteria, can be trapped [4, 5]. Clara cells produce the surfactant apoproteins A and B and secretory leukoprotease inhibitor. In addition, these cells may participate in the clearance of noxious agents via the detoxification of inhaled agents [6-8]. Serous cells also produce anti-proteases [9], whereas neuroendocrine cells contain amines and peptide hormones [10-12]. The mucous cell is the predominant secretory cell in the larger airways, whereas the Clara cell is predominant in the bronchioles [2, 13, 14].

Basal cells are considered as the stem cell of the bronchial epithelium and are pyramidal-shaped cells with a low cytoplasmic/nuclear ratio [2, 15, 16].

BARRIER FUNCTIONS

Bronchial epithelial cells are part of the non-specific immune system and defend the airways against the entry of noxious substances [17]. This defense is mediated via the integrity of the epithelium that contributes to the physical barrier, the secretion and ciliary function leading to effective mucociliary clearance, and the secretion of mediators which provide protection against a wide range of potentially injurious agents.

Integrity of the epithelium

The bronchial epithelium forms a continuous layer, thereby protecting the underlying tissue from noxious agents. The integrity of the epithelium is maintained by several adhesion mechanisms [18]. The desmosome (macula adherence) and the intermediate junction (zonula adherence) are involved in maintaining a strong cell-to-cell adhesion. The tight junction (zonula occludens) is a narrow, belt-like structure surrounding each cell at the apical pole. It provides a physical barrier, thereby preventing "leakage". The epithelial cells are all anchored to the basement membrane by hemidesmosomes.

Mucociliary clearance

Inhaled particles, including bacteria and viruses, are cleared from the airways by trapping of the particle in mucus, and subsequent clearance of the mucus by the coordinated beating of cilia. The clearance of particles is facilitated by the secretion of surfactant (by alveolar epithelial type II cells and Clara cells), which changes the surface charge properties, making the particles less sticky. The mucociliary function is regulated by a variety of factors, such as bradykinin, histamine, and cytokines, such as interleukin (IL)-1 [19-23].

Secretion of protective mediators

To provide protection against potentially injurious agents, the bronchial epithelium secretes a number of mediators, including anti-bacterial substances (lactoferrin and lysozyme), anti-proteases (alpha₁-protease inhibitor, secretory leukoprotease inhibitor, alpha₁-anti-chymotrypsin, alpha₂-macroglobulin, tissue inhibitors of metalloproteases), and anti-oxidant systems (glutathione redox cycle, superoxide dismutase, and catalase) [24-28]. The bronchial epithelium produces components of the complement system, which act as opsonins allowing efficient phagocytosis by macrophages [29]. In addition, bronchial epithelial cells transport secretory immunoglobulin A (sIgA) into the bronchial lumen [30]. In lung cells of patients with asthma, a reduced expression of superoxide dismutase has been found compared to healthy controls [31, 32]. In contrast, sIgA and lactoferrin are increased in bronchoalveolar lavage (BAL) fluid of asthmatics [33]. The release of bronchoactive and immunomodulatory mediators, such as cytokines, arachidonic acid metabolites, and chemokines, will be discussed below.

Loss of barrier function in asthma

The barrier function of the bronchial epithelium is disturbed in asthmatics and epithelial shedding and loss of integrity are recognized features both in fatal asthma and in biopsy specimens of even mild asthmatics [34-38]. Epithelial shedding or damage is probably due to the release of cationic granule proteins by activated eosinophils, which are highly toxic to the respiratory epithelium [39-43]. Indeed, asthmatic airways are characterized by increased numbers of activated eosinophils and elevated levels of eosinophil-derived mediators [34, 44, 45]. Several studies have identified an association between epithelial damage and the degree of bronchial hyperresponsiveness [36-38, 45]. This association may be caused by several mechanisms. First, epithelial damage will result in loss of a permeability barrier enabling noxious agents or allergens to directly penetrate the airway wall and reach the submucosa. In the submucosa, these substances may activate inflammatory cells, which subsequently are able to release mediators that modulate bronchial smooth muscle tone. Second, epithelial damage may expose nonmyelinated afferent nerve endings. As a consequence, these nerves may more easily be stimulated by inflammatory mediators or inhaled particles, leading to an axon reflex and subsequent release of sensory neuropeptides that in turn evoke neurogenic inflammation [46]. Third, the epithelium secretes factors that suppress airway contraction, such as prostaglandin (PG) E₂, prostacyclin, nitric oxide (NO), and a putative epithelial-derived relaxing factor (EpDRF) [47]. Loss of these factors may contribute to bronchial hyperresponsiveness. Fourth, bronchial epithelial cells contain neutral endopeptidase (NEP), which is involved in the metabolism of a variety of peptides with contractile effects on smooth muscle [48, 49]. Epithelial damage and loss of NEP activity may diminish peptide breakdown and thereby enhance bronchoconstriction. Finally, epithelial damage may trigger the production and release of mediators, such as PGF_2alpha, 13-hydroxy-linoleic acid (HODE) and endothelin-1, which can affect airway responsiveness [50-53].

PRO-INFLAMMATORY POTENTIAL OF THE BRONCHIAL EPITHELIUM

Bronchial epithelial cells not only form a passive barrier but also play an active role in the immune response. They are able to produce a variety of mediators that may be either pro- or anti-inflammatory. Bronchial epithelial cells may initiate and perpetuate inflammatory reactions by recruitment of inflammatory cells, cell-cell adhesion and interaction of epithelial cells with inflammatory cells, and modulation of the activity of inflammatory or parenchymal cells.

Recruitment of inflammatory cells

The recruitment of inflammatory cells into the airways is dependent upon the presence of chemoattractants. It has been demonstrated that bronchial epithelial cells can synthesize and release a wide range of such chemoattractants, including arachidonic acid metabolites and chemokines, both spontaneously and after stimulation (Table 1).

Bronchial epithelial cells may secrete the arachidonic acid metabolites 15-hydroxyeicosatetranoic acid (15-HETE) and possibly leukotriene B₄ (LTB₄), which are potent attractants for eosinophils, neutrophils and monocytes, and also increase mucus secretion [54-62]. The production and release of these mediators is up-regulated in asthma, and there is a clear correlation between the release of 15-HETE and the clinical status of the patient [58].

Human bronchial epithelial cells are able to produce several chemokines, including RANTES (Regulated upon Activation, Normal T cell Expressed, and presumably Secreted) [63], growth regulated oncogen (Gro)-alpha [64], monocyte chemoattractant protein (MCP)-1 [64, 65], MCP-4 [66], IL-8 [67-69], and eotaxin [70].

Bronchial epithelial cells from asthmatics have been shown to release more IL-8 in vitro than epithelial cells obtained from healthy controls [69]. In addition, increased levels of IL-8 were demonstrated in BAL fluid of asthmatics [71]. Using immunohistochemical techniques, an increased expression of MCP-1 [65] and eotoaxin [72, 73] has been found in the bronchial epithelium of asthmatics. In contrast, no differences in RANTES protein or mRNA expression could be observed between healthy subjects and asthmatics [74]. Clearly, bronchial epithelial cells of asthmatic patients release increased amounts of CC and CXC chemokines and therefore contribute to the recruitment of inflammatory cells.

IL-16 is a recently discovered cytokine, which has been shown to have selective chemotactic activity for CD4-positive cells, monocytes, and eosinophils in vitro [75, 76]. IL-16, which shows no similarity to other cytokines or members of the chemokine family, uses CD4 as its receptor [75, 76]. In the lung, it is produced by epithelial cells, and CD4-positive and CD8-positive T lymphocytes [77]. Increased expression of IL-16 by bronchial epithelial cells has been described in asthmatics compared to healthy subjects, and the epithelial IL-16 expression was shown to correlate with the number of CD4-positive cells within the lamina propria [78]. In addition, IL-16 has been detected in BAL fluid six hours after subsegmental allergen or histamine challenge in asthmatics, but not in atopic non-asthmatics or healthy subjects [79].

Bronchial epithelial cells have also been shown to release platelet-activating factor (PAF), a potent eosinophil chemoattractant [80].

Cell-cell adhesion and interaction

Bronchial epithelial cells may interact with other cells by direct contact, mediated via surface membrane-bound molecules, such as adhesion molecules and major histocompatibility complex (MHC) molecules.

Adhesion molecules are glycoproteins expressed on the surface of cells, which mediate the contact between two cells or between the cell and the components of the extracellular matrix. These molecules therefore play an important role in the transmigration of leukocytes through the endothelial wall, localization of leukocytes at sites of inflammation in the epithelium, and adherence of the epithelial cells to the basement membrane. Four main families of adhesion molecules can be distinguished: the immunoglobulin-gene superfamily, the integrins, the selectins, and the cadherins [81].

The immunoglobulin (Ig)-gene superfamily consists of cell surface proteins characterized by a variable number of extracellular Ig-like domains [82, 83]. Human bronchial epithelial cells express two members of this family: intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-3 (LFA-3) [84]. It has been reported that the epithelial expression of ICAM-1 is increased in asthmatics compared to healthy subjects, and that the level of expression correlated with the severity of the disease [85, 86]. However, no difference in ICAM-1 expression was found in another study [87]. In the BAL fluid of asthmatics, increased levels of soluble ICAM-1 have been found after allergen challenge [88, 89]. Circulating ICAM-1 levels in the blood were elevated in patients with acute asthma compared to stable asthmatics or healthy subjects [89-91]. It has been shown that pro-inflammatory cytokines such as IL-1ß, TNF-alpha and IFN-gamma, are able to increase the expression of ICAM-1 on epithelial cells in vitro [84, 92, 93]. Since the ligand for ICAM-1, LFA-1 (CD11a/CD18), is expressed on the surface of neutrophils, monocytes, lymphocytes and eosinophils [94], increased expression of ICAM-1 during inflammatory responses may contribute to the adhesion and subsequent maturation and activation of leukocytes in the epithelial compartment. The observation that, in primates, intravenous administration of anti-ICAM-1 antibodies attenuated both airway eosinophilia and bronchial hyperresponsiveness further supports the important role of ICAM-1 in the recruitment and adhesion of leukocytes [85, 95]. In contrast to ICAM-1, LFA-3 expression on bronchial epithelial cells could not be modulated by pro-inflammatory cytokines [84] and its role in the pathogenesis of asthma remains to be established.

Integrins are molecules composed of two non-covalently associated heterodimers, designated the alpha and ß subunit [81, 94, 96]. ß₁ integrins may associate with nine distinct subunits and play an important role in tissue organization. Human bronchial epithelial cells have been shown to express the alpha_2-6 integrins, both in vivo and in vitro [95, 97-100]. In addition, recent studies have shown the expression of alpha_vß₆ on human bronchial epithelial cells [101, 102]. The expression of this adhesion molecule is increased after epithelial injury, inflammation or exposure to epidermal growth factor (EGF) or transforming growth factor (TGF)-ß. Studies using transgenic mice indicate that alpha_valpha₆ may be involved in the down-regulation of airway inflammation [103, 104]. ß₂ integrins (LFA-1 (alpha_Lß₂), Mac-1 (alpha_Mß₂), and p150,95 (alpha_Xß₂)) are exclusively expressed on leukocytes.

The selectin family (consisting of E- (endothelial), P- (platelet), and L- (leukocyte) selectin) is only expressed on activated endothelial cells or leukocytes [82, 105, 106]. No expression can be found on human bronchial epithelial cells [84].

Cadherins are involved in the cellular architecture and in cell-cell adhesion. Cadherins may interact with the cytoskeleton and bind to a group of cytosolic proteins termed catenins [107]. It has been suggested that alterations in the binding of epithelial cadherin to catenins may be involved in the desquamation and shedding of the epithelium associated with the airways of asthmatic subjects.

Human bronchial epithelial cells are also able to express the MHC class II antigens (including human leukocyte antigen (HLA)-DR) [62, 86]. Bronchial epithelial HLA-DR expression has been shown to be increased in asthmatic patients compared to healthy subjects, and the level of expression is correlated with the severity of the disease [86]. In vitro, the expression of MHC class II on human bronchial epithelial cells is relatively low, but after stimulation with IFN-gamma or histamine its expression is strongly increased [62, 108, 109]. Although it has been demonstrated that bronchial epithelial cells are capable of inducing T cell proliferation [110-112], it is not clear at present whether presentation of antigens to lymphocytes by bronchial epithelial cells is involved in the pathogenesis of asthma.

Expression of the low-affinity IgE receptor (CD23) has been described in bronchial epithelial cells from asthmatic patients, but not from healthy controls [113]. Stimulation of bronchial epithelial cells from asthmatics with IgE/anti-IgE resulted in increased release of endothelin-1 (ET-1). This suggests that bronchial epithelial cells from asthmatic patients may be directly activated by an IgE-dependent mechanism.

Modulation of inflammatory or parenchymal cell activity

Human bronchial epithelial cells are capable of producing a wide range of mediators, which are important in modulating cellular responses in the airways, both spontaneously and after stimulation. These mediators include chemokines, lipid mediators, cytokines, endothelins, growth factors, and NO (Table 1).

As mentioned before, chemokines are able to recruit leukocytes to the site of inflammation [114, 115]. These mediators often also activate the attracted leukocytes. For example, it has been shown that MCP-1 is able to activate monocytes and basophils, and can induce ICAM-1 expression on endothelial and vascular smooth muscle cells [116-119]. IL-8 and LTB₄ not only attract neutrophils, but also cause neutrophil degranulation and superoxide production, at least in vitro [120].

Lipid mediators produced by bronchial epithelial cells include the arachidonic acid metabolites LTB₄, 15-HETE, PGF_2alpha, and PGE₂ [61, 121-123]. PGE₂ plays a role in skewing T helper lymphocytes toward a Th2 phenotype. In addition, PGE₂ is a vasodilator, and its release may therefore result in the formation of oedema. 15-HETE increases the secretion of mucus and enhances an early response to inhaled allergens [124], whereas PGF_2alpha functions as a bronchoconstrictor [125, 126]. Prostacyclin and PGF_2alpha can stimulate sensory nerve endings, thereby causing reflex bronchoconstriction [127].

Bronchial epithelial cells can also produce and release a wide range of cytokines. These include granulocyte/macrophage-colony stimulating factor (GM-CSF), TNF-alpha, IL-1alpha, IL-1ß, IL-3, IL-6, IL-10, IL-11, leukemia inhibitory factor (LIF), and IL-16 [67, 69, 128-135]. GM-CSF production by the bronchial epithelium has been shown to be increased in asthmatics [69, 128]. This may contribute to a prolonged survival of neutrophils and eosinophils with concomitant cell activation [136-138]. IL-1ß and TNF-alpha are pro-inflammatory cytokines, which may activate a large number of cells. IL-6 and IL-11 have many overlapping effects, including B cell activation and production of acute phase proteins [139-141]. In addition, IL-11 has neuropoietic properties: it is a survival factor for sensory and motor neurons, causes noradrenergic sympathetic neurons to take on a cholinergic phenotype, and induces substance P (SP), somatostatin, and vasoactive intestinal peptide-related peptide in sympathetic neurons [142]. This raises the possibility that dysregulated IL-11 production could lead to pathological conditions characterized by cholinergic or neuropeptide excess. IL-16 not only attracts CD4-positive lymphocytes, eosinophils and monocytes but also activates these cells, resulting in cell adhesion, induction of CD25 and HLA-DR expression, and/or cytokine synthesis [76].

Bronchial epithelial cells of asthmatic patients have been shown to produce increased levels of IL-1ß, IL-6, IL-8, GM-CSF, and IL-16 compared to healthy subjects [69, 78, 143]. This indicates that bronchial epithelial cells are in an activated state in the asthmatic airways. Transcription factors such as nuclear factor (NF)kappaB probably play an important role in the upregulation of these cytokines [144, 145]. Interestingly, a recent report showed that the allergen Der p1 induced NFkappaB activation through interference with IkappaBalpha function in asthmatic bronchial epithelial cells, indicating that allergens may directly interact with transcription factors involved in the transcriptional regulation of inflammatory genes [146].

Endothelins are a family of highly homologous 21-amino acid peptides, characterized by two intrachain disulfide chains, a hairpin loop consisting of polar amino acids, and a hydrophobic C-terminal chain [147]. Human bronchial epithelial cells have been shown to produce ET-1 [51, 148, 149], which promotes the proliferation of smooth muscle cells, is a potent constrictor of both vascular and non-vascular smooth muscle cells, increases the secretion of mucus, and may activate inflammatory cells [147, 149, 150]. ET-1 also stimulates collagen gene expression and through its inhibitory actions on collagenase will promote airway wall collagen deposition, thereby contributing to airway wall thickening which underlies bronchial hyperresponsiveness [151-153]. Increased levels of ET-1-immunoreactivity were detected in airway epithelium and vascular endothelium of bronchial biopsy specimens from asthmatics compared to healthy subjects [148, 154, 155]. Furthermore, increased ET-1 levels have been detected in BAL fluid and blood plasma of asthmatics [156, 157].

The bronchial epithelium produces several growth factors. These include EGF, TGF-ß, insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) [17, 158, 159]. TGF-ß is an important profibrotic growth factor, which has been implicated in airway remodeling and pulmonary fibrosis [160]. In asthma, there is an increased expression of TGF-ß on epithelial cells which is correlated with the number of fibroblasts beneath the basement membrane and with the thickness of the basement membrane [155, 161, 162]. TGF-ß has been shown to increase the release of fibronectin from human bronchial epithelial cells in vitro [163]. IGF also is a major fibroblast and epithelial cell mitogen, but a role for this growth factor in asthma has not yet been determined. However, it has been shown that airway epithelial cells express increased numbers of IGF-receptors after stimulation with eosinophil cationic protein [164]. Studies on PDGF, which has high mitogenic activity for smooth muscle cells and fibroblasts, have not demonstrated any upregulation in the expression of this growth factor in the bronchial epithelium of asthmatics [162, 165, 166]. In contrast, epithelial cells of asthmatics do show increased immunoreactivity for EGF, which is an important factor in the regulation of epithelial growth and differentiation [165].

NO may play an important role in regulating airway function and in the pathophysiology of asthma [167-170]. NO is produced by nitric oxide synthase (NOS), which exists in several isoforms: n (neuronal)-NOS, e (endothelial)-NOS, and i (inducible)-NOS [171, 172]. Both the inducible and constitutive form have been identified in bronchial epithelial cells [173-175] and increased expression of iNOS has been observed in response to pro-inflammatory cytokines and oxidants [169, 175, 176]. There is an increased expression of iNOS in the epithelium of asthmatic patients and increased NO levels have been found in exhaled air of asthmatics [173, 177, 178]. Increased NO production in the airways may result in hyperemia, plasma exudation, and mucus secretion. NO also has been implicated in skewing T lymphocytes towards a Th2 phenotype, through inhibition of Th1 cells and their production of IFN-gamma [179].

ANTI-INFLAMMATORY POTENTIAL OF THE BRONCHIAL EPITHELIUM

Besides the potential of human bronchial epithelial cells to recruit and activate leukocytes or parenchymal cells, bronchial epithelial cells may also down-regulate inflammatory responses. This may occur via the release of anti-inflammatory mediators, by the release of soluble receptors, or by the inactivation of pro-inflammatory mediators.

Release of anti-inflammatory mediators

Human bronchial epithelial cells are able to produce several components of the IL-1 system, including agonists, antagonists and receptors. As discussed before, human bronchial epithelial cells can release IL-1alpha and IL-1ß, which both exert many pro-inflammatory effects. These effects are mediated via binding to the IL-1 receptor (IL-1R) type I, whereas the IL-1R type II has a short cytoplasmic domain and appears to function as a scavenger for IL-1ß [180-182]. The extracellular portions of both receptors may be shed from the plasma membrane and then act as IL-1 inhibitors [183]. Three splice variants of the IL-1 receptor antagonists (IL-1Ra) gene have been described thus far: secreted IL-1Ra, intracellular IL-1R type I and type II. It has been shown that human bronchial epithelial cells are able to produce and release the intracellular IL-1 receptor antagonists type I, which may counteract the pro-inflammatory actions of IL-1alpha and IL-ß [143, 184, 185]. Recently, a new cytokine (IL-18) with structural homology to IL-1 has been found [186, 187]. This cytokine requires cleavage by either IL-1ß converting enzyme or another caspase to generate a mature bioactive molecule, and signals through IL-1 receptor-associated kinase (IRAK) to induce activation of NFkappaB [188]. Clearly, the balance of the different components of the IL-1 system determines whether the overall effect will be pro- or anti-inflammatory.

TGF-ß has been identified in the epithelial lining fluid of the lung and in airway epithelial cells [189, 190]. In addition to its pro-inflammatory effects (described above), TGF-ß has many anti-inflammatory properties, including inhibition of IL-2-dependent proliferation of T lymphocytes, inhibition of cytokine production by macrophages, and inhibition of IL-4-induced IL-8 release by human bronchial epithelial cells [191-195]. TGF-ß may also be involved in neural repair via stimulation of IL-11 production by bronchial epithelial cells [134].

PGE₂ and IL-6 produced by bronchial epithelial cells may have both pro- and anti-inflammatory properties. PGE₂ can reduce the production of neutrophil chemoattractants by macrophages, can act directly as a bronchodilator (as does prostacyclin), and inhibits fibroblast matrix production [196, 197]. IL-6 has been found to reduce inflammatory reactions in several models, including an in vivo model of pulmonary inflammation [195]. However, the mechanism by which IL-6 exerts this effect is not completely understood.

IL-10 is a potent regulatory cytokine that decreases inflammatory responses and T cell activation [198-200]. It reduces the production of TNF-alpha and IL-1ß by macrophages [201-203]. Down-regulation of IL-10 production, as has been described in patients with cystic fibrosis [133], may enhance local inflammation and tissue damage.

Interactions between epithelial cells may be of primary importance in directing repair of injury. Fibronectin, together with growth factors, is thought to have a significant role in the modulation of epithelial cell migration. Its production is increased after injury and after exposure of epithelial cells to inflammatory mediators, such as cytokines and endothelin-1 [58, 131, 204-206].

NO produced by bronchial epithelial cells may also have beneficial effects. It increases the ciliary beat frequency, thereby facilitating the clearance of mucus with trapped agents [19]. NO is also a potent bronchodilator [169, 207]. In contrast to guinea pigs, human studies have failed to demonstrate that EpDRF is identical to NO [208-211].

Release of soluble receptors

The release of soluble receptors is another mechanism to control inflammatory processes [212, 213]. Soluble receptors may bind their ligand, thereby reducing the amount of ligand able to bind membrane-bound receptors. Bronchial epithelial cells have been shown to release the IL-6 receptor and the p55 (type I) soluble TNF-alpha receptor (sTNF-R), which may down-regulate the effects of IL-6 and TNF-alpha, respectively [214-216]. In a study with stable asthmatic children, no difference in sTNF-R levels in serum could be observed compared to healthy subjects [217]. However, during asthma exacerbations serum levels of sTNF-R were significantly increased in both non-atopic and atopic asthmatics [218].

Inhibition of pro-inflammatory mediators

Bronchial epithelial cells express several enzymes which are able to degrade, and thereby often inactivate, a variety of peptides, including neuropeptides, histamine, bradykinin, and cytokines. Epithelial cells express histamine N-methyltransferase, and thus are capable of modulating histamine-mediated effects [219, 220]. The best-studied peptidase expressed by bronchial epithelial cells is NEP. NEP plays an important role in the modulation of neurogenic inflammation, and a reduced activity of this enzyme has been implicated in the pathogenesis of asthma [49, 221, 222]. Indeed, many of the agents that lead to exacerbations of asthma, including viruses, cigarette smoke and chemical irritants, appear to reduce the activity of NEP in the airways (reviewed in [223]) and thereby contribute to exaggerated neurogenic inflammatory responses.

CONCLUSION

The bronchial epithelium defends the airways against the entry of noxious agents. This defense is mediated via the integrity of the bronchial epithelium, the mucociliary clearance, and the secretion of protective mediators. In the past decade it has become clear that bronchial epithelial cells may also contribute to inflammatory processes in the airways. Bronchial epithelial cells are able to recruit inflammatory cells, to express surface molecules that are involved in cell-cell adhesion and interaction, and to modulate the activity of inflammatory or parenchymal cells. Conversely, bronchial epithelial cells may control inflammatory reactions in the airway by the release of anti-inflammatory mediators, the release of soluble receptors, and the inhibition or inactivation of pro-inflammatory mediators. The potent inflammatory potential of the bronchial epithelium may provide a mechanism to rapidly initiate inflammatory reactions if the barrier function of the epithelium is disturbed and noxious or infectious agents may stimulate bronchial epithelial cells.

In patients with asthma, epithelial loss or damage may result in exposure of sensory nerves, reduced degradation of (neuro)peptides, loss of factors that relax airway smooth muscle, and increased production of factors affecting airway responsiveness (Figure 1). As a consequence, the airways may become hyperresponsive, which is a key feature of asthmatic patients. Loss of barrier function may also expose the bronchial epithelium to a variety of stimuli, thereby triggering the inflammatory potential of the epithelium. Indeed, bronchial epithelial cells from asthmatic patients release increased amounts of inflammatory mediators and express increased levels of adhesion molecules on their surface compared to healthy controls, thereby contributing to the inflammatory process characteristic of the asthmatic airways. Further studies on the role of the bronchial epithelium in inflammatory reactions will eventually lead to a better understanding of these cells in the pathophysiology of asthma and may provide new directions in asthma drug therapy.

Acknowledgments

We gratefully acknowledge Mr. T.M. van Os for preparing the figures.

REFERENCES

1. Bai A, Eidelman D H, Hogg J C, James A L, Lambert R K, Ludwig M S, Martin J, McDonald D M, Mitzner W A, Oka-
zawa M, Pack R J, Paré P D, Schellenberg R R, Tiddens H A W, Wagner E M, Yager D. 1994. Proposed nomenclature for quantifying subdivisions of the bronchial wall. J. Appl. Physiol. 77: 1011.

2. Ayers M M, Jeffer P K. 1988. Proliferation and differentiation in mammalian airway epithelium. (Review) Eur. Respir. J. 1: 58.

3. Inayama Y, Hook G E, Brody A R, Jetten A M, Gray T, Mahler J, Nettesheim P. 1989. In vitro and in vivo growth and differentiation of clones of tracheal basal cells. Am. J. Pathol. 134: 539.

4. McDowell E M, Barrett L A, Glavin F, Harris C C, Trump B F. 1978. The respiratory epithelium. I. Human bronchus. J. Natl. Cancer Inst. 61: 539.

5. Harkema J R. 1991. Comparative aspects of nasal airway anatomy: relevance to inhalation toxicology. (Review) Toxicol. Pathol. 19: 321.

6. Franken C, Meijer C J, Dijkman J H. 1989. Tissue distribution of anti-leukoprotease and lysozyme in humans. J. Histochem. Cytochem. 37: 493.

7. Beckmann J D, Spurzem J R, Rennard S I. 1993. Phenol sulfotransferase expression in the airways: enzymological and immunohistochemical demonstration. Cell Tissue Res. 274: 475.

8. De Water R, Willems L N, van Muijen G N, Franken C, Fransen J A, Dijkman J H, Kramps J A. 1986. Ultrastructural localization of bronchial anti-leukoprotease in central and peripheral human airways by a gold-labeling technique using monoclonal antibodies. Am. Rev. Respir. Dis. 133: 882.

9. Rogers A V, Dewar A, Corrin B, Jeffery P K. 1993. Identification of serous-like cells in the surface epithelium of human bronchioles. Eur. Respir. J. 6: 498.

10. Boers J E, den Brok J L, Koudstaal J, Arends J W, Thunnissen F B. 1996. Number and proliferation of neuroendocrine cells in normal human airway epithelium. Am. J. Respir. Crit. Care Med. 154: 758.

11. Lauweryns J M, de Bock V, Verhofstad A A, Steinbusch H W. 1982. Immunohistochemical localization of serotonin in intrapulmonary neuro-epithelial bodies. Cell Tissue Res. 226: 215.

12. Tsutsumi Y, Osamura R Y, Watanabe K, Yanaihara N. 1983. Simultaneous immunohistochemical localization of gastrin releasing peptide (GRP) and calcitonin (CT) in human bronchial endocrine-type cells. Virchows Arch. A. Pathol. Anat. Histopathol. 400: 163.

13. Jeffery P K. 1983. Morphologic features of airway surface epithelial cells and glands. Am. Rev. Respir. Dis. 128: S14.

14. Widdicombe J G, Pack R J. 1982. The Clara cell. Eur. J. Respir. Dis. 63: 202.

15. Thompson A B, Robbins R A, Romberger D J, Sisson J H, Spurzem J R, Teschler H, Rennard S I. 1995. Immunological functions of the pulmonary epithelium. (Review) Eur. Respir. J. 8: 127.

16. Breuer R, Zajicek G, Christensen T G, Lucey E C, Snider G L. 1990. Cell kinetics of normal adult hamster bronchial epithelium in the steady state. Am. J. Respir. Cell Mol. Biol. 2: 51.

17. Rennard S I, Romberger D J, Sisson J H, Von Essen S G, Rubinstein I, Robbins R A, Spurzem J R. 1994. Airway epithelial cells: functional roles in airway disease. (Review) Am. J. Respir. Crit. Care Med. 150: S27.

18. Roche W R, Montefort S, Baker J, Holgate S T. 1993. Cell adhesion molecules and the bronchial epithelium. Am. Rev. Respir. Dis. 148: S79.

19. Jain B, Rubinstein I, Robbins R A, Sisson J H. 1995. TNF-alpha and IL-1 beta upregulate nitric oxide-dependent ciliary motility in bovine airway epithelium. Am. J. Physiol. 268: L911.

20. Burman W J, Martin W J. 2d 1986. Oxidant-mediated ciliary dysfunction. Possible role in airway disease. Chest 89: 410.

21. Sanderson M J, Dirksen E R. 1989. Mechanosensitive and beta-adrenergic control of the ciliary beat frequency of mammalian respiratory tract cells in culture. Am. Rev. Respir. Dis. 139: 432.

22. Khan A R, Bengtsson B, Lindberg S. 1986. Influence of substance P on ciliary beat frequency in airway isolated preparations. Eur. J. Pharmacol. 130: 91.

23. Mussatto D J, Garrard C S, Lourenco R V. 1988. The effect of inhaled histamine on human tracheal mucus velocity and bronchial mucociliary clearance. Am. Rev. Respir. Dis. 138: 775.

24. Coonrod J D. 1986. The role of extracellular bactericidal factors in pulmonary host defense. (Review) Semin. Respir. Infect. 1: 118.

25. Ellison R T 3d, Giehl T J. 1991. Killing of gram-negative bacteria by lactoferrin and lysozyme. J. Clin. Invest. 88: 1080.

26. Heffner J E, Repine J E. 1989. Pulmonary strategies of anti-oxidant defense. (Review) Am. Rev. Respir. Dis. 140: 531.

27. Arnold R R, Cole M F, McGhee J R. 1977. A bactericidal effect for human lactoferrin. Science 197: 263.

28. Bullen J J, Armstrong J A. 1979. The role of lactoferrin in the bactericidal function of polymorphonuclear leucocytes. Immunology 36: 781.

29. Rothman B L, Merrow M, Bamba M, Kennedy T, Kreutzer D L. 1989. Biosynthesis of the third and fifth complement components by isolated human lung cells. Am. Rev. Respir. Dis. 139: 212.

30. Goodman M R, Link D W, Brown W R, Nakane P K. 1981. Ultrastructural evidence of transport of secretory IgA across bronchial epithelium. Am. Rev. Respir. Dis. 123: 115.

31. Smith L J, Shamsuddin M, Sporn P H, Denenberg M, Anderson J. 1997. Reduced superoxide dismutase in lung cells of patients with asthma. Free Radic. Biol. Med. 22: 1301.

32. De Raeve H R, Thunnissen F B, Kaneko F T, Guo F H, Lewis M, Kavuru M S, Secic M, Thomassen M J, Erzurum S C. 1997. Decreased Cu, Zn-SOD activity in asthmatic airway epithelium: correction by inhaled corticosteroid in vivo. Am. J. Physiol. 272: L148.

33. Van de Graaf E A, Out T A, Kobesen A, Jansen H M. 1991. Lactoferrin and secretory IgA in the bronchoalveolar lavage fluid from patients with a stable asthma. Lung 169: 275.

34. Bousquet J, Chanez P, Lacoste J Y, Barneon G, Ghavanian N, Enander I, Venge P, Ahlstedt S, Simony-Lafontaine J, Godard P, Michel F B. 1990. Eosinophilic inflammation in asthma. N. Engl. J. Med. 323: 1033.

35. Beasley R, Roche W R, Roberts J A, Holgate S T. 1989. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am. Rev. Respir. Dis. 139: 806.

36. Jeffery P K, Wardlaw A J, Nelson F C, Collins J V, Kay A B. 1989. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am. Rev. Respir. Dis. 140: 1745.

37. Laitinen L A, Heino M, Laitinen A, Kava T, Haahtela T. 1985. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am. Rev. Respir. Dis. 131: 599.

38. Ohashi Y, Motojima S, Fukuda T, Makino S. 1992. Airway hyperresponsiveness, increased intracellular spaces of bronchial epithelium, and increased infiltration of eosinophils and lymphocytes in bronchial mucosa in asthma. Am. Rev. Respir. Dis. 145: 1469.

39. Frigas E, Loegering D A, Gleich G J. 1980. Cytotoxic effects of the guinea pig eosinophil major basic protein on tracheal epithelium. Lab. Invest. 42: 35.

40. Agosti J M, Altman L C, Ayars G H, Loegering D A, Gleich G J, Klebanoff S J. 1987. The injurious effect of eosinophil peroxidase, hydrogen peroxide, and halides on pneumocytes in vitro. J. Allergy Clin. Immunol. 79: 496.

41. Gleich G J, Flavahan N A, Fujisawa T, Vanhoutte P M. 1988. The eosinophil as a mediator of damage to respiratory epithelium: a model for bronchial hyperreactivity. (Review) J. Allergy Clin. Immunol. 81: 776.

42. Barnes P J. 1989. New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. (Review) J. Allergy Clin. Immunol. 83: 1013.

43. Motojima S, Frigas E, Loegering D A, Gleich G J. 1989. Toxicity of eosinophil cationic proteins for guinea pig tracheal epithelium in vitro. Am. Rev. Respir. Dis. 139: 801.

44. Bentley A M, Menz G, Storz C, Robinson D S, Bradley B, Jeffery P K, Durham S R, Kay A B. 1992. Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness. Am. Rev. Respir. Dis. 146: 500.

45. Wardlaw A J, Dunnette S, Gleich G J, Collins J V, Kay A B. 1988. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am. Rev. Respir. Dis. 137: 62.

46. Barnes P J. 1986. Asthma as an axon reflex. Lancet 1: 242.

47. Raeburn D, Webber S E. 1994. Proinflammatory potential of the airway epithelium in bronchial asthma. (Review) Eur. Respir. J. 7: 2226.

48. Baraniuk J N, Ohkubo K, Kwon O J, Mak J, Ali M, Davies R, Twort C, Kaliner M, Letarte M, Barnes P J. 1995. Localization of neutral endopeptidase (NEP) mRNA in human bronchi. Eur. Respir. J. 8: 1458.

49. Nadel J A, Borson D B. 1991. Modulation of neurogenic inflammation by neutral endopeptidase. (Review) Am. Rev. Respir. Dis. 143: S33.

50. Nadel J A. 1988. Some epithelial metabolic factors affecting airway smooth muscle. Am. Rev. Respir. Dis. 138: S22.

51. Mattoli S, Mezzetti M, Riva G, Allegra L, Fasoli A. 1990. Specific binding of endothelin on human bronchial smooth muscle cells in culture and secretion of endothelin-like material from bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 3: 145.

52. Henricks P A, Engels F, van der Vliet H, Nijkamp F P. 1991. 9- and 13-hydroxy-linoleic acid possess chemotactic activity for bovine and human polymorphonuclear leukocytes. Prostaglandins 41: 21.

53. Endo T, Uchida Y, Matsumoto H, Suzuki N, Nomura A, Hirata F, Hasegawa S. 1992. Regulation of endothelin-1 synthesis in cultured guinea pig airway epithelial cells by various cytokines. Biochem. Biophys. Res. Commun. 186: 1594.

54. Koyama S, Rennard S I, Leikauf G D, Shoji S, von Essen S, Claassen L, Robbins R A. 1991. Endotoxin stimulates bronchial epithelial cells to release chemotactic factors for neutrophils. A potential mechanism for neutrophil recruitment, cytotoxicity, and inhibition of proliferation in bronchial inflammation. J. Immunol. 147: 4293.

55. Koyama S, Rennard S I, Leikauf G D, Robbins R A. 1991. Bronchial epithelial cells release monocyte chemotactic activity in response to smoke and endotoxin. J. Immunol. 147: 972.

56. Alpert S E, Walenga R W. 1993. Human tracheal epithelial cells selectively incorporate 15-hydroxyeicosatetraenoic acid into phosphatidylinositol. Am. J. Respir. Cell Mol. Biol. 8: 273.

57. Alpert S E, Walenga R W. 1995. Ozone exposure of human tracheal epithelial cells inactivates cyclooxygenase and increases 15-HETE production. Am. J. Physiol. 269: L734.

58. Campbell A M, Chanez P, Vignola A M, Bousquet J, Couret I, Michel F B, Godard P. 1993. Functional characteristics of bronchial epithelium obtained by brushing from asthmatic and normal subjects. Am. Rev. Respir. Dis. 147: 529.

59. Shannon V R, Chanez P, Bousquet J, Holtzman M J. 1993. Histochemical evidence for induction of arachidonate 15-lipoxygenase in airway disease. Am. Rev. Respir. Dis. 147: 1024.

60. Ford-Hutchinson A W, Bray M A, Doig M V, Shipley M E, Smith M J. 1980. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 286: 264.

61. Holtzman M J. 1992. Arachidonic acid metabolism in airway epithelial cells. (Review) Annu. Rev. Physiol. 54: 303.

62. Vignola A M, Chanez P, Campbell A M, Bousquet J, Michel F B, Godard P. 1993. Functional and phenotypic characteristics of bronchial epithelial cells obtained by brushing from asthmatic and normal subjects. Allergy 48: 32.

63. Stellato C, Beck L A, Gorgone G A, Proud D, Schall T J, Ono S J, Lichtenstein L M, Schleimer R P. 1995. Expression of the chemokine RANTES by a human bronchial epithelial cell line. Modulation by cytokines and glucocorticoids. J. Immunol. 155: 410.

64. Becker S, Quay J, Koren H S, Haskill J S. 1994. Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am. J. Physiol. 266: L278.

65. Sousa A R, Lane S J, Nakhosteen J A, Yoshimura T, Lee T H, Poston R N. 1994. Increased expression of the monocyte chemoattractant protein-1 in bronchial tissue from asthmatic subjects. Am. J. Respir. Cell Mol. Biol. 10: 142.

66. Stellato C, Collins P, Ponath P D, Soler D, Newman W, La Rosa G, Li H, White J, Schwiebert L M, Bickel C, Liu M, Bochner B S, Williams T, Schleimer R P. 1997. Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines. J. Clin. Invest. 99: 926.

67. Cromwell O, Hamid Q, Corrigan C J, Barkans J, Meng Q, Collins P D, Kay A B. 1992. Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1 beta and tumour necrosis factor-alpha. Immunology 77: 330.

68. Levine S J, Larivee P, Logun C, Angus C W, Shelhamer J H. 1993. Corticosteroids differentially regulate secretion of IL-6, IL-8, and G-CSF by a human bronchial epithelial cell line. Am. J. Physiol. 265: L360.

69. Marini M, Vittori E, Hollemborg J, Mattoli S. 1992. Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J. Allergy Clin. Immunol. 89: 1001.

70. Lilly C M, Nakamura H, Kesselman H, Nagler-Anderson C, Asano K, Garcia-Zepeda E A, Rothenberg M E, Drazen J M, Luster A D. 1997. Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids. J. Clin. Invest. 99: 1767.

71. Yousefi S, Hemmann S, Weber M, Holzer C, Hartung K, Blaser K, Simon H U. 1995. IL-8 is expressed by human peripheral blood eosinophils. Evidence for increased secretion in asthma. J. Immunol. 154: 5481.

72. Mattoli S, Stacey M A, Sun G, Bellini A, Marini M. 1997. Eotaxin expression and eosinophilic inflammation in asthma. Biochem. Biophys. Res. Commun. 236: 299.

73. Lamkhioued B, Renzi P M, Abi-Younes S, Garcia-Zepada E A, Allakhverdi Z, Ghaffar O, Rothenberg M D, Luster A D, Hamid Q. 1997. Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation.
J. Immunol. 159: 4593.

74. Fahy J V, Figueroa D J, Wong H H, Liu J T, Abrams J S. 1997. Similar RANTES levels in healthy and asthmatic airways by immunoassay and in situ hybridization. Am. J. Respir. Crit. Care Med. 155: 1095.

75. Cruikshank W W, Center D M, Nisar N, Wu M, Natke B, Theodore A C, Kornfeld H. 1994. Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression. Proc. Natl. Acad. Sci. USA 91: 5109.

76. Center D M, Kornfeld H, Cruikshank W W. 1996. Interleukin-16 and its function as a CD4 ligand. (Review) Immunol. Today 17: 476.

77. Bellini A, Vittori E, Marini M, Ackerman V, Mattoli S. 1993. Intraepithelial dendritic cells and selective activation of Th2-like lymphocytes in patients with atopic asthma. Chest 103: 997.

78. Laberge S, Ernst P, Ghaffar O, Cruikshank W W, Kornfeld H, Center D M, Hamid Q. 1997. Increased expression of inter-
leukin-16 in bronchial mucosa of subjects with atopic asthma. Am. J. Respir. Cell Mol. Biol. 17: 193.

79. Cruikshank W W, Long A, Tarpy R E, Kornfeld H, Carroll M P, Teran L, Holgate S T, Center D M. 1995. Early identification of interleukin-16 (lymphocyte chemoattractant factor) and macrophage inflammatory protein-1 alpha (MIP1 alpha) in bronchoalveolar lavage fluid of antigen-challenged asthmatics. Am. J. Respir. Cell Mol. Biol. 13: 738.

80. Samet J M, Noah T L, Devlin R B, Yankaskas J R, McKinnon K, Dailey L A, Friedman M. 1992. Effect of ozone on platelet-activating factor production in phorbol-differentiated HL60 cells, a human bronchial epithelial cell line (BEAS S6), and primary human bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 7: 514.

81. Springer T A. 1990. Adhesion receptors of the immune system. (Review) Nature 346: 425.

82. Carlos T M, Harlan J M. 1994. Leukocyte-endothelial adhesion molecules. Blood 84: 2068.

83. Williams A F, Barclay A N. 1988. The immunoglobulin superfamily-domains for cell surface recognition. (Review) Annu. Rev. Immunol. 6: 381.

84. Bloemen P G, van den Tweel M C, Henricks P A, Engels F, Wagenaar S S, Rutten A A, Nijkamp F P. 1993. Expression and modulation of adhesion molecules on human bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 9: 586.

85. Wegner C D, Gundel R H, Reilly P, Haynes N, Letts L G, Rothlein R. 1990. Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma. Science 247: 456.

86. Vignola A M, Campbell A M, Chanez P, Bousquet J, Paul-Lacoste P, Michel F B, Godard P. 1993. HLA-DR and ICAM-1 expression on bronchial epithelial cells in asthma and chronic bronchitis. Am. Rev. Respir. Dis. 148: 689.

87. Montefort S, Herbert C A, Robinson C, Holgate S T. 1992. The bronchial epithelium as a target for inflammatory attack in asthma. (Review) Clin. Exp. Allergy 22: 511.

88. Takahashi N, Liu M C, Proud D, Yu X Y, Hasegawa S, Spannhake E W. 1994. Soluble intracellular adhesion molecule-1 in bronchoalveolar lavage fluid of allergic subjects following segmental antigen challenge. Am. J. Respir. Crit. Care Med. 150: 704.

89. Lee Y C, Cheon K T, Rhee Y K. 1997. Changes of soluble ICAM-1 levels in serum and bronchoalveolar lavage fluid from patients with atopic bronchial asthma after allergen challenge. J. Asthma 34: 405.

90. Shiota Y, Wilson J G, Marukawa M, Ono , Kaji M. 1996. Soluble intercellular adhesion molecule-1 (ICAM-1) antigen in sera of bronchial asthmatics. Chest 109: 94.

91. Montefort S, Gratziou C, Goulding D, Polosa R, Haskard D O, Howarth P H, Holgate S T, Carroll M P. 1994. Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways. J. Clin. Invest. 93: 1411.

92. Rothlein R, Czajkowski M, O'Neill M M, Marlin S D, Mainolfi E, Merluzzi V J. 1988. Induction of intercellular adhesion molecule-1 on primary and continuous cell lines by pro-inflammatory cytokines. Regulation by pharmacologic agents and neutralizing antibodies. J. Immunol. 141: 1665.

93. Atsuta J, Sterbinsky S A, Plitt J, Schwiebert L M, Bochner B S, Schleimer R P. 1997. Phenotyping and cytokine regulation of the BEAS-2B human bronchial epithelial cell: demonstration of inducible expression of the adhesion molecules VCAM-1 and ICAM-1. Am. J. Resp. Cell Mol. Biol. 17: 571.

94. Kishimoto T K, Larson R S, Corbi A L, Dustin M L, Staunton D E, Springer T A. 1989. The leukocyte integrins. (Review) Adv. Immunol. 46: 149.

95. Manolitsas N D, Trigg C J, McAulay A E, Wang J H, Jordan S E, D'Ardenne A J, Davies R J. 1994. The expression of intercellular adhesion molecule-1 and the beta 1-integrins in asthma. Eur. Respir. J. 7: 1439.

96. Albelda S M. 1991. Endothelial and epithelial cell adhesion molecules. (Review) Am. J. Respir. Cell Mol. Biol. 4: 195.

97. Mette S A, Pilewski J, Buck C A, Albelda S M. 1993. Distribution of integrin cell adhesion receptors on normal bronchial epithelial cells and lung cancer cells in vitro and in vivo. Am. J. Respir. Cell Mol. Biol. 8: 562.

98. Montefort S, Baker J, Roche W R, Holgate S T. 1993. The distribution of adhesive mechanisms in the normal bronchial epithelium. Eur. Respir. J. 6: 1257.

99. Pilewski J M, Latoche J D, Arcasoy S M, Albelda S M. 1997. Expression of integrin cell adhesion receptors during human airway epithelial repair in vivo. Am. J. Physiol. 273: L256.

100. Koukoulis G K, Warren W H, Virtanen I, Gould V E. 1997. Immunolocalization of integrins in the normal lung and in pulmonary carcinomas. Hum. Pathol. 28: 1018.

101. Sheppard D. 1996. Epithelial integrins. (Review) Bioessays 18: 655.

102. Weinacker A, Ferrando R, Elliott M, Hogg J, Balmes J, Sheppard D. 1995. Distribution of integrins alpha v beta 6 and alpha 9 beta 1 and their known ligands, fibronectin and tenascin, in human airways. Am. J. Respir. Cell Mol. Biol. 12: 547.

103. Huang X Z, Wu J F, Cass D, Erle D J, Corry D, Young S G, Farese R V Jr, Sheppard D. 1996. Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J. Cell. Biol. 133: 921.

104. Herard A L, Pierrot D, Hinnrasky J, Kaplan H, Sheppard D, Puchelle E, Zahm J M. 1996. Fibronectin and its alpha 5 beta
1-integrin receptor are involved in the wound-repair process of airway epithelium. Am. J. Physiol. 271: L726.

105. Bevilacqua M P, Nelson R M. 1993. Selectins. (Review) J. Clin. Invest. 91: 379.

106. Lasky L A. 1992. Selectins: interpreters of cell-specific carbohydrate information during inflammation. (Review) Science 258: 964.

107. Kemler R. 1993. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. (Review) Trends Genet. 9: 317.

108. Rossi G A, Sacco O, Balbi B, Oddera S, Mattioni T, Corte G, Ravazzoni C, Allegra L. 1990. Human ciliated bronchial epithelial cells: expression of the HLA-DR antigens and of the HLA-DR alpha gene, modulation of the HLA-DR antigens by gamma-interferon and antigen-presenting function in the mixed leukocyte reaction. Am. J. Respir. Cell Mol. Biol. 3: 431.

109. Spurzem J R, Sacco O, Rossi G A, Beckmann J D, Rennard S I. 1992. Regulation of major histocompatibility complex class II gene expression on bovine bronchial epithelial cells. J. Lab. Clin. Med. 120: 94.

110. Kalb T H, Chuang M T, Marom Z, Mayer L. 1991. Evidence for accessory cell function by class II MHC antigen-expressing airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 4: 320.

111. Nakajima J, Ono M, Kobayashi J, Kawauchi M, Takeda M, Furuse A, Takizawa H. 1996. Human allogenic airway epithelial cell line induces lymphocytes to secrete interleukin-10. Transplant. Proc. 28: 1861.

112. Nakajima J, Ono M, Takeda M, Kawauchi M, Furuse A, Takizawa H. 1997. Role of costimulatory molecules on airway epithelial cells acting as alloantigen-presenting cells. Transplant. Proc. 29: 2297.

113. Campbell A M, Vignola A M, Chanez P, Godard P, Bousquet J. 1994. Low-affinity receptor for IgE on human bronchial epithelial cells in asthma. Immunology 82: 506.

114. Sozzani S, Locati M, Allavena P, van Damme J, Mantovani A. 1996. Chemokines: a superfamily of chemotactic cytokines. (Review) Int. J. Clin. Lab. Res. 26: 69.

115. Baggiolini M, Dahinden C A. 1994. CC chemokines in allergic inflammation. (Review) Immunol. Today 15: 127.

116. Rollins B J, Walz A, Baggiolini M. 1991. Recombinant human MCP-1/JE induces chemotaxis, calcium flux, and the respiratory burst in human monocytes. Blood 78: 1112.

117. Rollins B J. 1992. "Oh, no. Not another cytokine." MCP-1 and respiratory disease. (Review) Am. J. Respir. Cell Mol. Biol. 7: 126.

118. Shyy Y J, Wickham L L, Hagan J P, Hsieh H J, Hu Y L, Telian S H, Valente A J, Sung K L, Chien S. 1993. Human monocyte colony-stimulating factor stimulates the gene expression of monocyte chemotactic protein-1 and increases the adhesion of monocytes to endothelial monolayers. J. Clin. Invest. 92: 1745.

119. Ikeda U, Ikeda M, Seino Y, Takahashi M, Kasahara T, Kano S, Shimada K. 1993. Expression of intercellular adhesion molecule-1 on rat vascular smooth muscle cells by pro-inflammatory cytokines. Atherosclerosis 104: 61.

120. Yoshimura K, Nakagawa S, Koyama S, Kobayashi T, Homma T. 1994. Roles of neutrophil elastase and superoxide anion in leukotriene B4-induced lung injury in rabbit. J. Appl. Physiol. 76: 91.

121. Churchill L, Chilton F H, Resau J H, Bascom R, Hubbard W C, Proud D. 1989. Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells. Am. Rev. Respir. Dis. 140: 449.

122. Hunter J A, Finkbeiner W E, Nadel J A, Goetzl E J, Holtzman M J. 1985. Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea. Proc. Natl. Acad. Sci. USA 82: 4633.

123. Salari H, Chan-Yeung M. 1989. Release of 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin E2 (PGE2) by cultured human bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 1: 245.

124. Lai C K, Polosa R, Holgate S T. 1990. Effect of 15-(s)-hydroxyeicosatetraenoic acid on allergen-induced asthmatic responses. Am. Rev. Respir. Dis. 141: 1423.

125. Haye-Legrand I, Cerrina J, Raffestin B, Labat C, Boullet C, Bayol A, Benveniste J, Brink C. 1986. Histamine contraction of isolated human airway muscle preparations: role of prostaglandins. J. Pharmacol. Exp. Ther. 239: 536.

126. Coleman R A, Sheldrick R L. 1989. Prostanoid-induced contraction of human bronchial smooth muscle is mediated by TP-receptors. Br. J. Pharmacol. 96: 688.

127. Mapp C E, Fabbri L M, Boniotti A, Maggi C A. 1991. Prostacyclin activates tachykinin release from capsaicin-sensitive afferents in guinea-pig bronchi through a ruthenium red-sensitive pathway. Br. J. Pharmacol. 104: 49.

128. Soloperto M, Mattoso V L, Fasoli A, Mattoli S. 1991. A bronchial epithelial cell-derived factor in asthma that promotes eosinophil activation and survival as GM-CSF. Am. J. Physiol. 260: L530.

129. Woolley K L, Adelroth E, Woolley M J, Ramis I,
Abrams J S, Jordana M, O'Byrne P M. 1996. Interleukin-3 in bronchial biopsies from nonasthmatics and patients with mild and allergen-induced asthma. Am. J. Respir. Crit. Care Med. 153: 350.

130. Devalia J L, Campbell A M, Sapsford R J, Rusznak C, Quint D, Godard P, Bousquet J, Davies R J. 1993. Effect of nitrogen dioxide on synthesis of inflammatory cytokines expressed by human bronchial epithelial cells in vitro. Am. J. Respir. Cell Mol. Biol. 9: 271.

131. Noah T L, Paradiso A M, Madden M C, McKinnon K P, Devlin R B. 1991. The response of a human bronchial epithelial cell line to histamine: intracellular calcium changes and extracellular release of inflammatory mediators. Am. J. Respir. Cell Mol. Biol. 5: 484.

132. Bellini A, Yoshimura H, Vittori E, Marini M, Mattoli S. 1993. Bronchial epithelial cells of patients with asthma release chemoattractant factors for T lymphocytes. J. Allergy Clin. Immunol. 92: 412.

133. Bonfield T L, Konstan M W, Burfeind P, Panuska J R, Hilliard J B, Berger M. 1995. Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is downregulated in cystic fibrosis. Am. J. Respir. Cell Mol. Biol. 13: 257.

134. Elias J A, Zheng T, Whiting N L, Trow T K, Merrill W W, Zitnik R, Ray P, Alderman E M. 1994. IL-1 and transforming growth factor-beta regulation of fibroblast-derived IL-11. J. Immunol. 152: 2421.

135. Knight D, McKay K, Wiggs B, Schellenberg R R, Bai T. 1997. Localization of leukaemia inhibitory factor to airway epithelium and its amplification of contractile responses to tachykinins. Br. J. Pharmacol. 120: 883.

136. Cox G, Gauldie J, Jordana M. 1992. Bronchial epithelial cell-derived cytokines (G-CSF and GM-CSF) promote the survival of peripheral blood neutrophils in vitro. Am. J. Respir. Cell Mol. Biol. 7: 507.

137. Cox G, Ohtoshi T, Vancheri C, Denburg J A, Dolovich J, Gauldie J, Jordana M. 1991. Promotion of eosinophil survival by human bronchial epithelial cells and its modulation by steroids. Am. J. Respir. Cell Mol. Biol. 4: 525.

138. Nakamura Y, Azuma M, Okano Y, Sano T, Takahashi T, Ohmoto Y, Sone S. 1996. Upregulatory effects of interleukin-4 and interleukin-13 but not interleukin-10 on granulocyte/macrophage colony-stimulating factor production by human bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 15: 680.

139. Anderson K C, Morimoto C, Paul S R, Chauhan D, Williams D, Cochran M, Barut B A. 1992. Interleukin-11 promotes accessory cell-dependent B-cell differentiation in humans. Blood 80: 2797.

140. Baumann H, Schendel P. 1991. Interleukin-11 regulates the hepatic expression of the same plasma protein genes as interleukin-6. J. Biol. Chem. 266: 20424.

141. Neben S, Turner K. 1993. The biology of interleukin-11. (Review) Stem Cells 11: 156.

142. Patterson P H, Nawa H. 1993. Neuronal differentiation factors/cytokines and synaptic plasticity. (Review) Cell 72: 123.

143. Sousa A R, Lane S J, Nakhosteen J A, Lee T H, Poston R N. 1996. Expression of interleukin-1 beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1Ra) on asthmatic bronchial epithelium. Am. J. Respir. Crit. Care Med. 154: 1061.

144. Manni A, Kleimberg J, Ackerman V, Bellini A, Patalano F, Mattoli S. 1996. Inducibility of RANTES mRNA by IL-1beta in human bronchial epithelial cells is associated with increased NFkappaB DNA binding activity. Biochem. Biophys. Res. Commun. 220: 120.

145. Lenardo M J, Baltimore D. 1989. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. (Review) Cell 58: 227.

146. Stacey M A, Sun G, Vassalli G, Marini M, Bellini A, Mattoli S. 1997. The allergen Der p1 induces NF-kappa B activation through interference with I kappa B alpha function in asthmatic bronchial epithelial cells. Biochem. Biophys. Res. Commun. 236: 522.

147. Gandhi C R, Berkowitz D E, Watkins W D. 1994. Endothelins. Biochemistry and pathophysiologic actions. (Review) Anesthesiology 80: 892.

148. Vittori E, Marini M, Fasoli A, de Franchis R, Mattoli S. 1992. Increased expression of endothelin in bronchial epithelial cells of asthmatic patients and effect of corticosteroids. Am. Rev. Respir. Dis. 146: 1320.

149. Hay D W, Hubbard W C, Undem B J. 1993. Endothelin-induced contraction and mediator release in human bronchus. Br. J. Pharmacol. 110: 392.

150. Barnes P J. 1994. Endothelins and pulmonary diseases. (Review) J. Appl. Physiol. 77: 1051.

151. Mansoor A M, Honda M, Saida K, Ishinaga Y, Kuramochi T, Maeda A, Takabatake T, Mitsui Y. 1995. Endothelin induced collagen remodeling in experimental pulmonary hypertension. Biochem. Biophys. Res. Commun. 215: 981.

152. Rizvi M A, Katwa L, Spadone D P, Myers P R. 1996. The effects of endothelin-1 on collagen type I and type III synthesis in cultured porcine coronary artery vascular smooth muscle cells. J. Mol. Cell. Cardiol. 28: 243.

153. Dawes K E, Cambrey A D, Campa J S, Bishop J E, McAnulty R J, Peacock A J, Laurent G J. 1996. Changes in collagen metabolism in response to endothelin-1: evidence for fibroblast heterogeneity. Int. J. Biochem. Cell. Biol. 28: 229.

154. Springall D R, Howarth P H, Counihan H, Djukanovic R, Holgate S T, Polak J M. 1991. Endothelin immunoreactivity of airway epithelium in asthmatic patients. Lancet 337: 697.

155. Redington A E, Springall D R, Meng Q H, Tuck A B, Holgate S T, Polak J M, Howarth P H. 1997. Immunoreactive endothelin in bronchial biopsy specimens: increased expression in asthma and modulation by corticosteroid therapy. J. Allergy Clin. Immunol. 100: 544.

156. Redington A E, Springall D R, Ghatei M A, Lau L C, Bloom S R, Holgate S T, Polak J M, Howarth P H. 1995. Endothelin in bronchoalveolar lavage fluid and its relation to airflow obstruction in asthma. Am. J. Respir. Crit. Care Med. 151: 1034.

157. Kraft M, Beam W R, Wenzel S E, Zamora M R, O'Brien R F, Martin R J. 1994. Blood and bronchoalveolar lavage endothelin-1 levels in nocturnal asthma. Am. J. Respir. Crit. Care Med. 149: 946.

158. Nettesheim P, Ferriola P, Steigerwalt R, Robertson A, Rundhaug J. 1992. The role of growth factors in the regulation of proliferation of tracheobronchial epithelium. Chest 101: 23S.

159. Sacco O, Romberger D, Rizzino A, Beckmann J D, Rennard S I, Spurzem J R. 1992. Spontaneous production of transforming growth factor-beta 2 by primary cultures of bronchial epithelial cells. Effects on cell behavior in vitro. J. Clin. Invest. 90: 1379.

160. Kovacs E J. 1991. Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. (Review) Immunol. Today 12: 17.

161. Campbell A M. 1997. Bronchial epithelial cells in asthma. (Review) Allergy 52: 483.

162. Vignola A M, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A, la Rocca A M, Bellia V, Bonsignore G, Bousquet J. 1997. Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med. 156: 591.

163. Adachi Y, Mio T, Takigawa K, Striz I, Romberger D J, Robbins R A, Spurzem J R, Heires P, Rennard S I. 1997. Mutual inhibition by TGF-beta and IL-4 in cultured human bronchial epithelial cells. Am. J. Physiol. 273: L701.

164. Chihara J, Urayama O, Tsuda A, Kakazu T, Higashimoto I, Yamada H. 1996. Eosinophil cationic protein induces insulin-like growth factor-I receptor expression on bronchial epithelial cells. Int. Arch. Allergy Immunol. 111: 43.

165. Bousquet J, Vignola A M, Chanez P, Campbell A M, Bonsignore G, Michel F B. 1995. Airways remodelling in asthma: no doubt, no more? (Review) Int. Arch. Allergy Immunol. 107: 211.

166. Chanez P, Vignola M, Stenger R, Vic P, Michel F B, Bousquet J. 1995. Platelet-derived growth factor in asthma. Allergy 50: 878.

167. Barnes P J, Liew F Y. 1995. Nitric oxide and asthmatic inflammation. (Review) Immunol. Today 16: 128.

168. Barnes P J. 1995. Nitric oxide and asthma. (Review) Res. Immunol. 146: 698.

169. Gaston B, Drazen J M, Loscalzo J, Stamler J S. 1994. The biology of nitrogen oxides in the airways. (Review) Am. J. Respir. Crit. Care Med. 149: 538.

170. Nijkamp F P, Folkerts G. 1994. Nitric oxide and bronchial reactivity. (Review) Clin. Exp. Allergy 24: 905.

171. Moncada S, Palmer R M, Higgs E A. 1991. Nitric oxide: physiology, pathophysiology, and pharmacology. (Review) Pharmacol. Rev. 43: 109.

172. Lowenstein C J, Snyder S H. 1992. Nitric oxide, a novel biologic messenger. (Review) Cell 70: 705.

173. Hamid Q, Springall D R, Riveros-Moreno V, Chanez P, Howarth P, Redington A, Bousquet J, Godard P, Holgate S, Polak J M. 1993. Induction of nitric oxide synthase in asthma. Lancet 342: 1510.

174. Kobzik L, Bredt D S, Lowenstein C J, Drazen J, Gaston B, Sugarbaker D, Stamler J S. 1993. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am. J. Respir. Cell Mol. Biol. 9: 371.

175. Robbins R A, Barnes P J, Springall D R, Warren J B, Kwon O J, Buttery L D, Wilson A J, Geller D A, Polak J M. 1994. Expression of inducible nitric oxide in human lung epithelial cells. Biochem. Biophys. Res. Commun. 203: 209.

176. Adcock I M, Brown C R, Kwon O, Barnes P J. 1994. Oxidative stress induces NF-kappa B DNA binding and inducible NOS mRNA in human epithelial cells. Biochem. Biophys. Res. Commun. 199: 1518.

177. Kharitonov S A, Yates D, Robbins R A, Logan-Sinclair R, Shinebourne E A, Barnes P J. 1994. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 343: 133.

178. Persson M G, Zetterstrom O, Agrenius V, Ihre E, Gustafsson L E. 1994. Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 343: 146.

179. Taylor-Robinson A W, Liew F Y, Severn A, Xu D, McSorley S J, Garside P, Padron J, Phillips R S. 1994. Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. Eur. J. Immunol. 24: 980.

180. Sims J E, March C J, Cosman D, Widmer M B,
Mac Donald H R, McMahan C J, Grubin C E, Wignall J M, Jackson J L, Call S M, Friend D, Alpert A, Gillis S, Urdal D L, Dower S. 1988. cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science 241: 585.

181. McMahan C J, Slack J L, Mosley B, Cosman D, Lupton S D, Brunton L L, Grubin C E, Wignall J M, Jenkins N A, Brannan C I, Copeland N G, Huebner K, Croce C M, Cannizzarro L A, Benjamin D, Dower S, Spriggs M, Sims J. 1991. A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J. 10: 2821.

182. Colotta F, Re F, Muzio M, Bertini R, Polentarutti N, Sironi M, Giri J G, Dower S K, Sims J E, Mantovani A. 1993. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 261: 472.

183. Symons J A, Eastgate J A, Duff G W. 1991. Purification and characterization of a novel soluble receptor for inter-
leukin-1. J. Exp. Med. 174: 1251.

184. Levine S J, Benfield T, Shelhamer J H. 1996. Corticosteroids induce intracellular interleukin-1 receptor antagonist type I expression by a human airway epithelial cell line. Am. J. Respir. Cell Mol. Biol. 15: 245.

185. Levine S J, Wu T, Shelhamer J H. 1997. Extracellular release of the type I intracellular IL-1 receptor antagonist from human airway epithelial cells : differential effects of IL-4,
IL-13, IFN-gamma, and corticosteroids. J. Immunol. 158: 5949.

186. Bazan J F, Timans J C, Kastelein R A. 1996. A newly defined interleukin-1? Nature 379: 591.

187. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K, et al. 1996. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378: 88.

188. Robinson D, Shibuya K, Mui A, Zonin F, Murphy E, Sana T, Hartley S B, Menon S, Kastelein R, Bazan F, O'Garra A. 1997. IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NF-kappa B. Immunity 7: 571.

189. Yamauchi K, Martinet Y, Basset P, Fells G A, Crystal R G. 1988. High levels of transforming growth factor-beta are present in the epithelial lining fluid of the normal human lower respiratory tract. Am. Rev. Respir. Dis. 137: 1360.

190. Khalil N, O'Connor R N, Unruh H W, Warren P W, Flanders K C, Kemp A, Bereznay O H, Greenberg A H. 1991. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 5: 155.

191. Adachi M, Matsukura S, Tokunaga H, Kokubu F. 1997. Expression of cytokines on human bronchial epithelial cells induced by influenza virus A. Int. Arch. Allergy Immunol. 113: 307.

192. Kehrl J H, Wakefield L M, Roberts A B, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn M B, Fauci A S. 1986. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J. Exp. Med. 163: 1037.

193. Espevik T, Figari I S, Shalaby M R, Lackides G A, Lewis G D, Shepard H M, Palladino M A Jr. 1987. Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J. Exp. Med. 166: 571.

194. Strober W, Kelsall B, Fuss I, Marth T, Ludviksson B, Ehrhardt R, Neurath M. 1997. Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. (Review) Immunol. Today 18: 61.

195. Ulich T R, Yin S, Guo K, Yi E S, Remick D, del Castillo J. 1991. Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation. Am. J. Pathol. 138: 1097.

196. Christman J W, Christman B W, Shepherd V L, Rinaldo J E. 1991. Regulation of alveolar macrophage production of chemoattractants by leukotriene B4 and prostaglandin E2. Am. J. Respir. Cell Mol. Biol. 5: 297.

197. Florio C, Martin J G, Styhler A, Heisler S. 1994. Anti-proliferative effect of prostaglandin E2 in cultured guinea pig tracheal smooth muscle cells. Am. J. Physiol. 266: L131.

198. de Vries J E. 1995. Immunosuppressive and anti-inflammatory properties of interleukin-10. (Review) Ann. Med. 27: 537.

199. Mosmann T R. 1994. Properties and functions of interleukin-10. Adv. Immunol. 56: 1.

200. Pretolani M, Goldman M. 1997. IL-10: a potential therapy for allergic inflammation? (Review) Immunol. Today 18: 277.

201. Bogdan C, Vodovotz Y, Nathan C. 1991. Macrophage deactivation by interleukin-10. J. Exp. Med. 174: 1549.

202. Bogdan C, Paik J, Vodovotz Y, Nathan C. 1992. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J. Biol. Chem. 267: 23301.

203. Oswald I P, Wynn T A, Sher A, James S L. 1992. Interleukin-10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation. Proc. Natl. Acad. Sci. USA 89: 8676.

204. Shoji S, Rickard K A, Ertl R F, Robbins R A, Linder J, Rennard S I. 1989. Bronchial epithelial cells produce lung fibroblast chemotactic factor: fibronectin. Am. J. Respir. Cell Mol. Biol. 1: 13.

205. Shoji S, Ertl R F, Linder J, Romberger D J, Rennard S I. 1990. Bronchial epithelial cells produce chemotactic activity for bronchial epithelial cells. Possible role for fibronectin in airway repair. Am. Rev. Respir. Dis. 141: 218.

206. Marini M, Carpi S, Bellini A, Patalano F, Mattoli S. 1996. Endothelin-1 induces increased fibronectin expression in human bronchial epithelial cells. Biochem. Biophys. Res. Commun. 220: 896.

207. Dupuy P M, Shore S A, Drazen J M, Frostell C, Hill W A, Zapol W M. 1992. Bronchodilator action of inhaled nitric oxide in guinea pigs. J. Clin. Invest. 90: 421.

208. Stuart-Smith K. 1990. Heterogeneity in epithelium-dependent responses. (Review) Lung 168: 43.

209. Raeburn D. 1990. Putative role of epithelial derived factors in airway smooth muscle reactivity. (Review) Agents Actions Suppl 31: 259.

210. Morrison K J, Gao Y, Vanhoutte P M. 1990. Epithelial modulation of airway smooth muscle. Am. J. Physiol. 258: L254.

211. Goldie R G, Fernandes L B, Farmer S G, Hay D W. 1990. Airway epithelium-derived inhibitory factor. (Review) Trends Pharmacol. Sci. 11: 67.

212. Rose-John S, Heinrich P C. 1994. Soluble receptors for cytokines and growth factors: generation and biological function. (Review) Biochem. J. 300: 281.

213. Debets R, Savelkoul H F. 1994. Cytokine antagonists and their potential therapeutic use. Immunol. Today 15: 455.

214. Takizawa H, Ohtoshi T, Yamashita N, Oka T, Ito K. 1996. Interleukin 6-receptor expression on human bronchial epithelial cells: regulation by IL-1 and IL-6. Am. J. Physiol. 270: L346.

215. Arnold R, Humbert B, Werchau H, Gallati H, Konig W. 1994. Interleukin-8, interleukin-6, and soluble tumour necrosis factor receptor type I release from a human pulmonary epithelial cell line (A549) exposed to respiratory syncytial virus. Immunology 82: 126.

216. Levine S J, Logun C, Chopra D P, Rhim J S, Shelhamer J H. 1996. Protein kinase C, interleukin-1 beta, and corticosteroids regulate shedding of the type I, 55 kDa TNF receptor from human airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 14: 254.

217. Laan M P, Koning H, Baert M R M, Oranje A P, Buur-
man W A, Savelkoul H F, Neijens H J. 1998. Levels of soluble intercellular adhesion molecule-1, soluble E-selectine, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptor p55 and p75 in atopic children. Allergy 53: 51.

218. Yoshida S, Hashimoto S, Nakayama T, Kobayashi T, Koizumi A, Horie T. 1996. Elevation of serum soluble tumour necrosis factor (TNF) receptor and IL-1 receptor antagonist levels in bronchial asthma. Clin. Exp. Immunol. 106: 73.

219. Okayama M, Yamauchi K, Sekizawa K, Okayama H, Sasaki H, Inamura N, Maeyama K, Watanabe T, Takishima T, Shirato K. 1995. Localization of histamine N-methyltransferase messenger RNA in human nasal mucosa. J. Allergy Clin. Immunol. 95: 96.

220. Ohrui T, Yamauchi K, Sekizawa K, Ohkawara Y, Maeyama K, Sasaki M, Takemura M, Wada H, Watanabe T, Sasaki H. 1992. Histamine N-methyltransferase controls the contractile response of guinea pig trachea to histamine. J. Pharmacol. Exp. Ther. 261: 1268.

221. Borson D B. 1991. Roles of neutral endopeptidase in airways. (Review) Am. J. Physiol. 260: L212.

222. Joos G F, Kips J C, Pauwels R A. 1994. A role for neutral endopeptidase in asthma? (Review) Clin. Exp. Allergy 24: 91.

223. Lilly C M, Drazen J M, Shore S A. 1993. Peptidase modulation of airway effects of neuropeptides. (Review) Proc. Soc. Exp. Biol. Med. 203: 388.