American Journal of Respiratory and Critical Care Medicine

In the 1980s, studies in the vascular field revealed that the endothelium was not simply a metabolic and physical barrier, but liberated substances that could modulate the function of underlying vascular smooth muscle. Investigators in the respiratory field also found that the airway epithelium was more than a physical barrier to airborne insults. The epithelium is composed of at least eight different cell types that have a range of functions, including ciliary motility and mucous secretion, and contain enzymes for liberating arachidonic acid metabolites and peptides. The epithelium also contains degradative enzymes for a number of peptides and biological amines. It was also recognized that the epithelium released substances that, like their vascular counterparts, could regulate the function of a number of cell types, including nerves and airway smooth muscle. These studies document the importance the epithelium plays in the regulation of human airway smooth muscle. Spina D. Epithelium smooth muscle regulation and interactions.

The airway epithelium consists of a heterogeneous population of cells that form tight junctions, thereby impeding access to underlying structures and acting as a physical barrier to foreign insults (1), and that perform diverse functions, including ciliary motility, mucous secretion, and ion transport (2, 3). Airway epithelial cells, including dendritic cells, express major histocompatibility complex (MHC) class I and II molecules, which endow the epithelium with the properties of an immunologic barrier (4, 5). The epithelium contains degradative enzymes, including neutral endopeptidase, which metabolize a wide range of biologically active peptides (6, 7), enzymes involved in sulfate conjugation (8), and oxidative enzymes, such as cytochrome P-450 monooxygenase (9, 10).

The epithelium is capable of synthesizing a variety of biologically active substances, including arachidonic acid metabolites (11), nonprostanoid inhibitory factor(s) (12), nitric oxide (13), endothelin (14), cytokines (15, 16), and growth factors (16, 17). It would be expected that these mediators regulate the function of immune cells, inflammatory cells, vascular smooth muscle, neuronal cells, and airway smooth muscle. A considerable body of evidence indicates that the epithelium can modulate the function of airway smooth muscle in a number of species (18). This review will highlight studies that provide evidence that the epithelium can modulate the function of human airway smooth muscle.

Arachidonic Acid Metabolites

The airway epithelium is a heterogeneous population of metabolically active cells capable of synthesizing and releasing a number of prostanoid and lipoxygenase products (11). Thus, bradykinin, the calcium-ionophore A23187 (19), arachidonic acid (20, 21), and platelet-activating factor (PAF) (21) stimulate the release of prostanoids from human cultured tracheal and bronchial epithelial cells. The cellular targets for epithelium-derived prostanoids remain to be established. The cyclooxygenase inhibitor indomethacin failed to alter spontaneously generated tone (22), but did increase tone in the presence of a 5-lipoxygenase inhibitor, indicating that under certain circumstances prostanoids released by the epithelium may alter airway smooth muscle tone (23). Cyclooxygenase inhibition with indomethacin did not, however, alter the increased airway sensitivity to acetylcholine following epithelium removal (24), suggesting that epithelium-derived prostanoids do not directly modulate the sensitivity of nondiseased human airway smooth muscle to contractile agonists. In contrast, the exogenous administration of prostaglandin (PG)E2 attenuated contractile responses mediated by cholinergic stimulation of human airways (25, 26), and the release of acetylcholine from cholinergic nerves appears to be augmented in the presence of indomethacin (27). Thus, prostanoids may indirectly alter airway smooth muscle tone via an action on cholinergic nerves.

The ability of human airway epithelium to synthesize products of the 15-lipoxygenase pathway (28) is consistent with the demonstration of 15-lipoxygenase immunoreactivity in basal and ciliated epithelial cells (29, 30). 15-Hydroxyeicosatetraenoic acid (15-HETE) is the predominant lipoxygenase metabolite released from cultured bronchial epithelial cells in response to arachidonic acid, bradykinin, acetylcholine, and PAF (20, 31). The release of 15-HETE from human epithelium by PAF was sufficient to induce contraction of airway smooth muscle.

It is also clear that leukotriene (LT)A4 hydrolase is expressed in cell lines and primary cultures of human airway epithelium (32). Furthermore, γ-glutamyl transpeptidase-like activity has been demonstrated in cultured human tracheal epithelial cells (33) and is responsible for the conversion of LTC4 to LTD4, while aminopeptidases may be responsible for the conversion of LTD4 to LTE4 (33). While the cysteinyl leukotrienes, products of the 5-lipoxygenase pathway, are responsible for the spontaneously generated tone of human bronchial tissues, the epithelium does not appear to be the sole source of these lipid-derived mediators, since basal tone was significantly reduced by 5-lipoxygenase inhibitors in epithelium-denuded human bronchial preparations (23). The leukotriene synthesis inhibitor AA861 and the leukotriene receptor antagonist ONO1078 reversed the gradual and continuous reduction of contractions evoked by nerve stimulation in epithelium-intact tissue, suggesting that leukotrienes may play a modulatory role on cholinergic nerves in the dog (34). It remains to be established whether leukotrienes can modulate cholinergic neurotransmission in humans.

Isolated Airway Preparations

It was originally demonstrated by Orehek and coworkers (35) that the mechanical irritation of the epithelium releases prostanoids, including PGE2 and PGF, which contract rat stomach strips in superfusion cascade. Furthermore, inhibition of cyclooxygenase enzyme augments the contractile response to both histamine and 5-hydroxytryptamine in guinea pig trachea (35). These data suggested that epithelium-derived arachidonic acid metabolites modulate airway smooth muscle function. Since then, a vast body of evidence has accumulated from studies in a variety of airway preparations in a number of species that physical removal of the epithelium results in an increase in the contractile potency to various spasmogens (18).

Removal of the epithelium resulted in an increase in contractile response to histamine (36-38) and to the muscarinic agonists, including acetylcholine, methacholine, and bethanechol (36-41), but not carbachol (38), in human airway preparations. The increase in sensitivity to acetylcholine occurred in the presence of indomethacin and the nitric oxide synthesis inhibitor, NG-nitro l-arginine methyl ester (l-NAME), thereby ruling out prostanoids and nitric oxide as inhibitory factors in this response (24). To what extent epithelium-derived acetylcholinesterases play a role in modulating the contractile response to acetylcholine is not clear, but an important role seems unlikely in view of the ability of the calcium-activated potassium channel blocker, iberiotoxin, to inhibit the increase in airway smooth muscle sensitivity to acetylcholine following epithelium removal (24). In contrast, the threefold increase in contractile responsiveness to LTD4 that followed epithelium removal from human isolated bronchi was indomethacin-sensitive (42), although epithelium removal failed to alter airway sensitivity to LTC4 or LTE4. Another study showed that epithelium removal augmented the contractile response to LTC4 and that this was mimicked in the presence of l-serine borate, providing evidence for γ-glutamyl transpeptidase-like activity in human airway epithelium (33). Differences in the degree of epithelium integrity observed in control tissues may have accounted for the discrepancies in these studies.

In contrast, epithelium removal was without effect on the relaxant potency to isoprenaline in human bronchial preparations (36), demonstrating that physical removal of the epithelium does not damage the underlying airway smooth muscle.

Bioassay Studies

The release of prostanoids following mechanical irritation of guinea pig epithelium and their transfer to rat stomach in superfusion cascade (35) and the transfer of bronchodilator prostanoids from epithelium intact to epithelium-denuded guinea pig trachea (43) and canine bronchus (44) in sandwich experiments have been documented. Superfusion cascade experiments have also demonstrated the release of inhibitory factor(s) from canine bronchus that are able to relax both vascular and airway smooth muscle preparations (45), although in other studies the transfer of inhibitory substances from guinea pig trachea stimulated by histamine (46) and antigen (47) was not observed. Recently, the transfer of an inhibitory factor from human cultured epithelial cells has been demonstrated in superfusion bioassay system. While the exact nature of this factor remains to be established, the inhibitory factor released from cultured epithelial cells appears to be neither prostanoid nor nitric oxide (24). Interestingly, this factor, which is spontaneously released in superfusion cascade, is dependent on intracellular calcium and on opening of calcium-activated potassium channels. This implies that hyperpolarization of airway epithelium is conducive to the release of a nonprostanoid inhibitory factor.

In contrast to the findings of Undem and colleagues (47) and Holroyde (46), Ilhan and Sahin (48) demonstrated the release of a nonprostanoid inhibitory factor(s) that relaxed an endothelium-denuded aorta mounted within an epithelium- intact guinea pig tracheal segment (coaxial bioassay). Acetylcholine, but not histamine, mediated the release of a nonprostanoid inhibitory factor(s) that relaxed phenylephrine-contracted rabbit endothelium-denuded aorta, and the epithelium dependence of this response was confirmed when it was shown that epithelium removal abolished the ability of acetylcholine to relax rabbit aorta (48). A similar technique was used by Hay and associates (49) to demonstrate that the ovalbumin-induced contraction of sensitized epithelium-denuded guinea pig trachea was attenuated by approximately sixfold when surrounded by an epithelium-intact guinea pig tracheal segment, suggesting that inhibitory factors generated by the donor preparation functionally antagonized the contraction of the sensitized epithelium-denuded preparation. Furthermore, the transfer of a nonprostanoid inhibitory factor(s) to rat anococcygeus (50) and guinea pig tracheal smooth muscle (51) has been demonstrated in a coaxial bioassay system. Moreover, a nonprostanoid factor that relaxes vascular smooth muscle has been shown to be released from guinea pig trachea (52, 53) and rabbit bronchus (54), but not from rat trachea (55). Similarly, human bronchial preparations have also been demonstrated to release an epithelium-dependent, nonprostanoid inhibitory factor that relaxed vascular smooth muscle (37, 52).

The exact nature of this nonprostanoid inhibitory factor(s) is not known, although it is not an arachidonic acid metabolite, PAF, nitric oxide, oxygen-derived free radicals, nor cytochrome P-450 monooxygenase products of arachidonic acid (52, 53). The relaxation observed in coaxial bioassay is associated with a small rise in the intracellular level of cyclic guanosine 3′,5′-monophosphate (cGMP) in vascular smooth muscle (56). Furthermore, the relaxant response and the associated increase in the levels of intracellular cGMP are not inhibited by the soluble guanylate cyclase inhibitor, methylene blue, suggesting the activation of particulate guanylate cyclase (56).

Recently it has been suggested that the relaxant response triggered by spasmogens in coaxial bioassay might be attributable to hypoxia (57). Thus, oxygen tension is significantly reduced within the lumen of epithelium-intact but not denuded airway segments, and this is exacerbated by spasmogen-induced constriction of the airway (57). However, this hypothesis is not consistent with a number of findings. Not all spasmogens mediate the release of an epithelium-derived, nonprostanoid inhibitory factor(s) in coaxial bioassay; acetic and carbamic choline esters and histamine, but not leukotrienes and substance P, mediate the release of an epithelium-derived inhibitory factor(s) from airway epithelium (53, 55). Furthermore, relaxant responses are not observed with rat tracheal preparations in coaxial bioassay (55). Additionally, the ATP-sensitive potassium channel blocker, glibenclamide, attenuates hypoxia-induced vascular relaxation but has no effect on the relaxant response observed in coaxial bioassay (58). Similarly, no rise in the intracellular levels of cGMP was observed in vascular smooth muscle under hypoxic conditions, although a small rise in the intracellular levels of cGMP was observed in coaxial bioassay experiments (56, 58). Together these results suggest that hypoxia alone cannot account for the relaxation observed in coaxial bioassay.

Removal of the epithelium fails to influence airway smooth muscle responsiveness to the carbamic choline ester, carbachol (59), although this spasmogen clearly stimulates the release of inhibitory factor(s) in coaxial bioassay (53). Thus, it has been hypothesized that the inhibitory factor(s) detected in stripping studies and in coaxial bioassay studies might be different. The airway epithelium may secrete at least two inhibitory factor(s), one that selectively modulates airway smooth muscle (45) and another that modulates vascular smooth muscle (12, 45, 55) function. The finding that inhibitory factor(s) can relax vascular smooth muscle has led to the speculation that these substances may be important in regulating blood flow beneath the airway epithelium, rather than in modulating airway smooth muscle tone (12, 55).

Human airway epithelium is also capable of synthesizing endothelin (60), which appears to be secreted from bronchial epithelium in culture (61). Functional studies have revealed that endothelin may regulate human airway smooth muscle tone directly by activation of receptors on airway smooth muscle (62) and indirectly via augmenting acetylcholine release from cholinergic nerves (63).

It is also clear that the epithelium is a potential source of smooth muscle growth factors, which may be released upon activation and/or damage to the structural integrity of the epithelium (16, 17). Thus, growth factors, including endothelin (64), platelet-derived growth factor (PDGF) (65), and epidermal growth factor (EGF) (66), stimulated the proliferation of human airway smooth muscle cells in culture. It has been suggested that, as a consequence of inflammatory insults to the airway, damage to the airway epithelium would signal the liberation of a number of growth factors that might promote the proliferation of airway smooth muscle, thereby leading to an alteration of airways responsiveness in vivo (17).

The epithelium is also a source of cytokines that can be released in response to chemical pollutants, bacterial products, and secondary to stimulation by cytokines (15). Using a variety of techniques, it is clear that under appropriate conditions the epithelium can secrete granulocyte macrophage colony-stimulating factor (GM-CSF), regulated on activation of normal T cell expressed and secreted (RANTES), IL-6, IL-8, and IL-1. These are all cytokines that can regulate the growth and recruitment of immunocompetent and/or inflammatory cells. The consequence of the release of these cytokines on airway smooth muscle function remains to be established. A mixture of cytokines, including interferon (IFN)-γ, IL-1β, and tumor necrosis factor (TNF)-α increased the expression of cyclooxygenase in human airway smooth muscle cells in culture, thereby leading to the synthesis of PGE2 (67). It remains to be established whether epithelial-derived cytokines can influence airway smooth muscle function directly and/or as a consequence of the eleboration of substances from this cell.

It is unclear whether epithelium-derived nitric oxide regulates human airway smooth muscle function. Nitric oxide, whether released from inhibitory NANC nerves or administered exogenously, relaxes human airway smooth muscle (68). However, a number of studies using conventional epithelium stripping, coaxial bioassay, and superfusion cascade fail to demonstrate a role for epithelium-derived nitric oxide in regulating the function of smooth muscle from central airways, and the possibility that nitric oxide regulates the function of more peripheral airways remains to be established.

The increase in airway smooth muscle sensitivity to spasmogens following epithelium removal in organ bath studies has also been attributed to the ability of the epithelium to act as a diffusion barrier (46, 69). However, a more direct assessment of the ability of the epithelium to act as a diffusion barrier is demonstrated in studies that examine the pharmacologic effect of agonists in perfused airway segments.

During the perfusion of guinea pig trachea under constant flow, the antigen-induced release of histamine was augmented following epithelium removal (47). Furthermore, airway smooth muscle sensitivity to contractile (59, 70, 71) and relaxant (72, 73) agonists was significantly increased following epithelium removal. Similarly, removal of the epithelium in airway segments perfused under conditions of constant pressure leads to an increase in airway smooth muscle sensitivity to contractile agonists in porcine, bovine (74), and human bronchi (75). the change in airway sensitivity to spasmogens such as histamine and acetylcholine following epithelium removal is one to two orders of magnitude greater than that observed in conventional stripping studies (59, 70, 71, 74, 75).

Thus, studies using perfused airway segments clearly demonstrate the ability of the epithelium to act as a diffusion barrier. However, the degree of protection afforded by the epithelium appears to be dependent on the lipophilicity of the agonist. Thus, the relaxant potency of hydrophobic β-adrenoceptor agonists, including terbutaline and salbutamol, are significantly attenuated when directed over the mucosal compared with the extraluminal surface (73, 76, 77), and the relaxant potency of salbutamol was increased 100-fold when administered via the mucosa in epithelium-denuded compared with epithelium-intact preparations (73). In contrast, the relaxant potency of lipophilic β-adrenoceptor agonists, including formoterol and salmeterol (76) and the methylxanthine, theophylline (73), is not influenced by the presence of the epithelium. Interestingly, it was shown that the epithelium acts as a diffusion barrier for cholinomimetics that are acetate esters, including acetylcholine and methacholine, but not for carbamoyl esters, including bethanechol and carbachol (59). It is not clear whether differences in the oil/water partition coefficient of these esters account for this finding.

The ability of the epithelium to release a nonprostanoid inhibitory factor(s) in perfusion studies appears to be dependent on the stimulus used. Thus, potassium ions are relatively ineffective in mediating contraction of epithelium-intact, perfused segments (59, 70-72, 74, 75). However, in precontracted perfused airway segments, osmotic stimuli such as potassium chloride and mannitol induce a relaxation response when applied intraluminally (70-72). The nature of this inhibitory factor(s) is unclear, although it is not a prostanoid. Furthermore, the relaxation response mediated by potassium ions is not inhibited by methylene blue or the nitric oxide synthesis enzyme inhibitor, N ω-monomethyl-l-arginine, but is attenuated by hemoglobin (70, 71, 78). Similarly, electrical-induced depolarization of epithelial cells releases an unidentified inhibitory factor(s) that is not an arachidonic acid metabolite, nor is it nitric oxide (34).

The role of the epithelium in modulating airway smooth muscle responsiveness to various peptides has received considerable interest in view of the possible role airway sensory nerves play in contributing to bronchial hyperresponsiveness in asthma. The close anatomic relationship between epithelial cells and sensory nerves and the localization of neutral endopeptidase to airway epithelium in human (79) makes this interaction amenable to study.

A number of studies have documented that epithelium removal augments the contractile potency to various sensory neuropeptides, including substance P and neurokinin A by one to two orders of magnitude in the guinea pig and ferret (18). Furthermore, the neutral endopeptidase inhibitors thiorphan and phosphoramidon can mimic the effect of epithelium removal, indicating that neutral endopeptidase is present within the epithelium. Moreover, viral infection of the respiratory epithelium or exposure to toluene di-isocyanate resulted in a reduction of neutral endopeptidase activity in the absence of overt loss in the integrity of the epithelium. The contractile response to exogenously administered neuropeptides was thereby augmented (18).

Epithelium removal also increased the contractile sensitivity to substance P and neurokinin A in human isolated bronchi, an effect that was mimicked by phosphoramidon (40), supporting the notion that the epithelium can modulate airway responsiveness to neuropeptides released from sensory nerves.

It is clear that the epithelium can modulate the function of human airway smooth muscle via the release of a number of bioactive substances that have excitatory and inhibitory activity. The epithelium also has the capacity to secrete a variety of growth factors that could stimulate airway smooth muscle proliferation and development of matrix-secreting phenotypes. These changes in airway smooth muscle function could impact on airway responsiveness.

Together this demonstrates the complexity of cell-to-cell interactions between airway epithelium and smooth muscle, which has both short- and long-term implications for the function of airway smooth muscle.

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Correspondence and requests for reprints should be addressed to The Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine, King's College School of Medicine and Dentistry, Bessemer Rd., London SE5 9PJ, UK. E-mail:

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American Journal of Respiratory and Critical Care Medicine
158
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