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ABSTRACT
The intercellular tight junction is the rate-limiting barrier in the paracellular pathway for permeation by ions and larger solutes. A variety of widely used electrical and flux approaches are used in the analyses of solute permeation through this pathway; however, each has limitations in practice. It is now clear that solute permeation across tight junctions is dynamically regulated by intracellular events with a common effector mechanism apparently tied to the cytoskeleton. These pathways, which regulate tight junction solute permeability, are targets that produce epithelial barrier dysfunction in a variety of disease states. However, regulation of solute permeation across the junctional barrier may also represent a potential means to improve bioavailability of orally administered bioactive solutes.
KEY WORDS: tight junctions, permeability, cytoskeleton, epithelia
INTRODUCTION
Solute transport across monolayers of columnar epithelia in vivo is often quantitatively astounding. The human intestine particularly exemplifies this. For example, consumption of meals and the subsequent osmotic equilibration of this intake in the proximal small intestine, coupled with endogenous secretions of hepatobiliary, gastroduodenal, pancreatic, and salivary origins, result in the delivery of approximately 9 liters of isosmotic fluid daily to this organ. Approximately 90% of this volume is absorbed over the small intestine surface, which correcting for surface amplifications, including villous projections and microvilli on individual cells, has a surface area of ==2 x 10^sup 6^ cm2. Because ==1 liter of fluid that passes the ileocecal valve and enters the colon remains essentially isosmotic, it follows that a vast solute transport occurs across this epithelium. Not only must the intestinal epithelium support such solute transport to assure nutrition, but it must perform this function while simultaneously serving as a barrier restricting free diffusion of potentially noxious environmental molecules.
Historically, a simplified view of this absorptive process was that transcellular movement of nutrients and water via specific pumps, transporters, and channels would account for absorption, while an impermeable tight junction seal adjoining epithelial cells would provide for the requisite barrier function (the biophysical nature of lipid bilayers is such that passive movement of hydrophilic solutes across the transcellular pathway is highly restricted). However, it has become increasingly clear that transjunctional solute movement does occur, that it occurs in a regulated fashion, and that its regulation in certain states...