In multicellular organisms, exchange between the cytoplasm of cells and the environment is facilitated by the vascular system in combination with the infolding of the surface epithelium to form the gastrointestinal, respiratory, and excretory (urinary) systems. These internalized, branching tubular pathways into the body of an organism are lined by continuous layers of cells, called epithelia, which preserve the boundary between the environment and the extracellular connective tissues and blood spaces. The epithelia lining these tubes are selectively permeable to molecules destined to be absorbed or secreted, by virtue of cellular transport systems that move these molecules through the cells between the inside and outside of the body. This route of transport of molecules through the epithelial cell cytoplasm is called the transcellular pathway. In addition to this route, molecules can move across epithelia by diffusing in between the cells [the so-called paracellular pathway (1)](Fig. 1). Although the spaces between epithelial cells are very narrow, typically 20–30 nm, the paracellular pathway nonetheless represents a significant leak between the environment and the connective tissues that must be regulated for the epithelium to remain selectively permeable. Organisms also subdivide their internal spaces into separate physiological compartments that do not communicate with the external environment. These internal compartments include the blood and lymphatic systems, the thoracic, pericardial, and abdominal cavities, and the specialized matrix that accompanies peripheral nerves. These compartments are likewise delimited by epithelioid layers of cells, termed endothelium, mesothelium, and perineurium.

The tight junction (zonula occludens) is the vertebrate gatekeeper of the paracellular pathway. Typically found at the most apical portion of epithelial cells’ lateral membranes, the tight junction is deployed as a belt around the circumference of each cell, joining all the cells, so that in the aggregate it forms a continuous, fishnet structure (Fig. 1, red). The structure of the tight junction has been characterized by using electron microscopy. Fig. 2 shows freeze-fracture and thin-section images of bile canaliculi in mouse liver, flanked by tight junctions. The membrane interactions appear as branching and anastomosing ‘‘strands’’on the P fracture face (above the canaliculus) and complementary grooves on the E fracture face (below the canaliculus). In thin section, the tight junctions can be seen to deny an experimentally administered extracellular tracer (horseradish peroxidase) access to the canalicular lumen (2). Epithelia and endothelia differ greatly in their ability to regulate gradients across their paracellular pathways. Depending on the functional requirements of an epithelium, there may be small or large amounts of water and small solutes flowing passively through the tight junctions (3). The resistance of the paracellular pathway also is dynamically regulated under different physiological conditions (4) and is accompanied by substantive cytoskeletal reorganization (5). Differences in the resistances of paracellular pathways found between different epithelia have been correlated with the freeze-fracture appearance of the junctional membranes, with the depth and complexity of the freeze-fracture strands being directly (6) or indirectly (7) responsible for resistances in series. Although elements of this correlation may be true, it also is known that