Involvement Of Ion Transport Mechanisms In Mediated Receptor Control Of Corneal Epithelial Cell Renewal And Volume Regulation

Identification of receptors that mediate control of corneal epithelial ion transporter function has been partially elucidated. There are adrenergic (11), serotonergic (12), and cholinergic (13) receptors that contribute to the control of ion transport activity. Regulation of ionic transport in frog corneal epithelia has been demonstrated to be under adrenergic control (14-16). Serotonergic control is shown by the finding that neural serotonin stimulates chloride transport in rabbit corneal epithelia (12). Endogenous cholinergic agonists are able to stimulate active ionic transport in rabbit corneal epithelia. Similarly, cholinergic receptors mediate regulation of epithelial cell proliferation (13, 17). Vital for perpetuation of corneal epithelial function are a host of cytokines that are released into the tears and anterior chamber from the epithelium and accessory tissues of the anterior ocular surface. Cytokine expression is critical for inducing control of proliferation and cell migration through stimulation of cognate receptors (18). Accordingly, control of cell proliferation and migration by cytokines and neuronal agonists is required for synchronization of the corneal epithelial renewal process and preservation of corneal epithelial functions. The uppermost epithelial layers are continuously being lost (into the tears during their terminal differentiation) and replaced, the latter process being necessary for maintenance of corneal transparency. Active ion transporters and channels are components of a myriad of cell signaling pathways that mediate cytokine receptor control of this renewal process (19, 20). Understanding of these events, coupled with the requirement for ion transport activity in maintaining corneal epithelial transparency, has prompted further studies into the mechanisms by which epithelial receptors elicit control of corneal epithelial renewal through stimulation of ion transport activity.

Synchronized epithelial renewal is essential for the maintenance of the cornea's multilayer integrity and function. Renewal of the upper epithelial layer preserves tight junctional resistance. In addition, epithelial renewal sustains receptor-mediated control of net ion transport, which is required for receptor modulation of epithelial membrane and tight junctional permeability (21). Should epithelial layer renewal become compromised, net ionic fluxes will decline as result of decreased ionic pump function, loss of membrane permselectivity, and decreased tight junctional electrical resistance (22).

Under physiological conditions, cellular losses due to terminal differentiation are countered by replacement with younger cells located in the inner cell layers. This renewal process ensures continuation of normal epithelial ion transport activity. Consequently, epithelial receptor-mediated control of renewal is required for the maintenance of corneal transparency and barrier function.

Even though the contribution of epithelial ion transport activity to deturgescence is much less than that of its endothelial counterpart, the epithelial component is required for the preservation of the integrity of the epithelial layers during exposure to anisosmotic stresses. Anisosmotic insults to the cornea frequently occur during activities of daily life, e.g., swimming or bathing, as well as from contact lens wear and ocular diseases such as dry eye syndrome (DES), as result of which, afflicted individuals experience chronic exposure to hypertonic tears. The physiological disturbances induced by such anisosmotic stresses are, very likely, counteracted by regulatory volume-response activation, such activity having been described in cultured corneal epithelial cells. Two different types of regulatory volume activations have been described for such an in vitro system. Exposure to a hypotonic challenge induces regulatory volume decrease (RVD) behavior, which acts to restore isotonic cell volume (23, 24). Such cell volume restoration is partially due to increases in K+ and Cl- membrane permeability, which results in KCl egress coupled to fluid loss. In human corneal epithelial cells, this regulatory response brings about complete recovery of isotonic cell volume within minutes of onset of the hypotonic stress. In contrast, cell exposure to hypertonic challenges, which simulate increased tear-film osmo-larity in DES (25), induces another type of regulatory volume response, referred to as the regulatory volume increase (RVI) (24, 26). Regulatory volume increase behavior restores the cell's isotonic volume through stimulation of ion and solute influx transport mechanisms, which mediate a rise in intracellular osmolyte content coupled with net fluid influx. Even though the RVI response is somewhat slower than the RVD response, corneal epithelial cells are able to achieve complete restoration of their isotonic volume following anisosmotic stress. In corneal epithelial cells, there is some evidence that specific receptors sense changes in osmolarity and activate a unique array of signaling pathways. These signaling pathways have some features in common to those linked to the cytokine receptors that mediate control of the corneal epithelial responses—proliferation and migration—required for renewal (27). This commonality—coupled with results from recent studies of other tissues, showing that cell volume regulation is requisite for proliferation and migration—suggests the importance of ion transport regulation in the maintenance of corneal epithelial function (28).

There is emerging evidence that receptor-mediated control of ion transport activity is requisite for corneal epithelial renewal (27, 29). This requirement is self-evident, since parent cell volume must increase to accommodate rises in genomic and cytoplasmic content prior to karyokinesis and cytokinesis. Similarly, changes in cell volume are requisite for cell migration, as this process involves repeated, coordinated leading-edge cytoplasmic volume extension, with retraction at the opposite pole. Because changes in ion transport activity underlie cell volume regulation, cytokine-induced control of renewal is, thus, dependent upon modulation of ion transport mechanisms. For this control to occur, corneal epithelial-induced cytokine expression of the corneal epithelium and accessory ocular tissues must be synchronized and manifested at appropriate times to alter cell volume, and to allow cell-cycle progression and migration to occur unperturbed. Numerous cytokines are involved in regulating these processes (18), some of which are needed to elicit control of proliferation and migration, while others affect rates of differentiation. Such controls occur through a host of cell-signaling pathways, each of which is specific for one of the cognate receptors. Any particular cytokine can elicit control of a variety of responses by activating different pathways within a cell-signaling network. The mitogen-activated protein kinase (MAPK) cascade is a superfamily of cytokines that mediates this type of exquisite control. Mitogen-activated protein kinase cascades have three different parallel pathways: the extracellular signal-regulated kinase (ERK); the p38; and the c-jun N-terminal/stress-activated protein kinase (JNK/SAPK) pathways. In corneal epithelial cells, different stimuli selectively activate specific receptors linked to one or more of these three different pathways. Cytokines that mediate increases in proliferation induce a response through stimulation of the ERK (i.e., p44/42) pathway, whereas those involved in increasing cell migration act through the p38 MAPK pathway (30-34). Stressors, such as anisosmotic challenges or apoptosis-inducing agents, e.g., ultraviolet light, activate the JNK/SAPK pathway (29, 35). Furthermore, the ability of a cytokine to elicit a particular response can be modulated by crosstalk between different branches of a cell-signaling network that is linked to different responses. Such

Growth Factor Stimulation

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