With a few exceptions, all internal and external body surfaces are covered with epithelium. This consists of a layer of structural protein, normally collagen, called the basal lamina, on which sit one or more layers of epithelial cells. There are several morphologically distinct common epithelial types (Figure 1.5):
a) Simple squamous epithelium. This forms a thin layer of flattened cells and consequently is relatively permeable. This type of epithelium lines most of the blood vessels.
b) Simple columnar epithelium. A single layer of columnar cells is found in the epithelium of organs such as the stomach and small intestine.
c) Transitional epithelium. This is composed of several layers of cells of different shapes and it lines epithelia which are required to stretch.
d) Stratified squamous epithelium. These membranes are several cells thick and are found in areas which have to withstand large amounts of wear and tear, for example the inside of the mouth and oesophagus, and the vagina. In the skin the outer cells become filled with keratin, and then die and slough off from the outside. This type of epithelium is termed keratinized and provides a major permeability barrier as well as protection from the environment.
Epithelial cells are said to be polarised due to the asymmetric distribution of transport proteins on the opposite ends of their plasma membranes. This causes the transport activity of the apical membrane of the cell to be different to that of the basolateral membrane. For example, nutrients absorbed across the intestinal epithelium have to cross two types of barrier to enter the blood from the lumen. At the apex of the cell, nutrients are actively transported into the cell by carrier-mediated mechanisms. At the base of the cell they are resecreted out of the cell and into the bloodstream by different transport proteins.
In the vast majority of tissues the cell membranes are not in close contact, but have an irregular intermembrane space of approximately 20 nanometres. Between this space lies the glycocalyx of the cells and a collection of glycoproteins and binding proteins such as fibronectin. In many tissues this space is bathed by the extracellular fluid and so is relatively permeable to small molecules. Drugs injected into a tissue of this type can diffuse with relative freedom. A typical example of this behaviour is the diffusion of drugs from an intramuscular injection, which rapidly spreads through the local muscle cells and into the
bloodstream. In epithelial tissues there is a need for a more effective chemical and physical barrier, and as a result the epithelial cells are bonded together by a number of different types of junctions which prevent diffusion of solutes around the cells. The primary types are (Figure 1.6):
a) tight junctions or zonulae occludens b) gap junctions c) desmosomes or zonulae adherens.
Tight junctions are formed when specific proteins in two adjacent plasma membranes make direct contact across the intercellular space (Figure 1.7). A belt-like structure composed of many protein strands completely encircles each cell in the epithelium, attaching it to its neighbours and sealing the outer (luminal) space from the interior of the tissue or organ. At a tight junction, the interacting plasma membranes are so closely apposed that there is no intercellular space and the membranes are within 2A of each other. As these junctions can be disrupted either by treatment with proteolytic enzymes or by agents that chelate Ca2+ or Mg2+, both the proteins and divalent cations are thought to be required for maintaining their integrity. Beneath the tight junction, the spaces between adjacent cells are wider5. The structure of the epithelium has been likened to "a six-pack of beer extended indefinitely in 2 dimensions"6.
Tight junctions play a critical part in maintaining the selective barrier function of cell sheets. For example, the epithelial cells lining the small intestine must keep most of the gut contents in the lumen. Simultaneously, the cells must pump selected nutrients across the cell
sheet into the extracellular fluid on the other side, from which they are absorbed into the blood. Studies have shown that the tight junctions are impermeable to colloidal particles, small molecules and ions, and possibly even to water. Electron microscopy shows that the junction consists of protein particles which are partly embedded in the membranes of both cells, so that the membranes become a single fused unit. As well as sealing the cells together, this prevents membrane proteins from the apical side of the cell diffusing to the basal side, maintaining the polarization of the cell.
The commonest type of cell junction is the gap junction, which is widely distributed in tissues of all animals (Figure 1.8). It is not so much an adhesion point between cells as a means by which cells may communicate via the exchange of cytoplasmic materials. Gap junctions consist of regions in which the gap between adjacent cell membranes narrows to approximately 2 to 3 nm, over a cross-sectional area of several hundred square nanometres. In this region both cell membranes contain a specialised protein called connexin, which forms tubular hexameric clusters with a central pore. These clusters are aligned in both membranes so that they form a path from one cell to another, through which cytoplasm and its solutes can be transferred.
Molecules up to 1200 Daltons can pass freely through the gaps but larger molecules cannot, suggesting a functioning pore size for the connecting channels of about 1.5 nm. Coupled cells share a variety of small molecules (such as inorganic ions, sugars, amino acids, nucleotides and vitamins) but do not share their macromolecules (proteins, nucleic acids and polysaccharides). ATP can pass between the cells, as can cyclic AMP, which mediates many types of hormonal control. Consequently, hormonal stimulation in just one or a few epithelial cells will initiate a metabolic response in many cells. Gap junctions close in the presence of high concentrations of Ca2+ ions, so that if a cell is damaged, the influx of extracellular calcium will seal the cell's gap junctions and prevent the leak extending through the tissue.
Figure 1.9 The desmosome
Figure 1.9 The desmosome
Desmosomes are small structures which bond adjacent cells together, and are most abundant in tissues that are subject to severe mechanical stress, such as cardiac muscle, skin epithelium and the neck of the uterus (Figure 1.9). They are widely distributed in tissues, and enable groups of cells to function as structural units. Desmosomes can be divided into three different types: spot desmosomes, belt desmosomes and hemidesmosomes, all three of which are present in most epithelial cells.
Belt desmosomes form a continuous band around each of the cells in an epithelial sheet, near the cell's apical end, typically just below the tight junction. The bands in adjacent cells are directly apposed and are separated by a poorly characterised filamentous material (in the intercellular space) that holds the interacting membranes together. Within each cell, contractile bundles of actin filaments run along the belts just under the plasma membrane and connect the structure to the cytoskeleton.
Spot desmosomes act like rivets to hold epithelial cells together at button-like points of contact. They also serve as anchoring sites for actin filaments which extend from one side of the cell to the other across the cell interior, forming a structural framework for the cytoplasm. Since other filaments extend from cell to cell at spot desmosomes, the actin filament networks inside adjacent cells are connected indirectly through these junctions to form a continuous network of fibres across the entire epithelial sheet.
Hemidesmosomes or half-desmosomes resemble spot desmosomes, but instead of joining adjacent epithelial cell membranes together, they join the basal surface of epithelial cells to the underlying basal lamina. Together spot desmosomes and hemidesmosomes act as bonds that distribute any shearing force through the epithelial sheet and its underlying connective tissue.
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