Lipid structures in the permeability barrier

Chapter 4 Lipid Structures in the Permeability Barrier Lars Norlen 31... 

D. T. Downing, Lipid and protein structures in the permeability barrier of mammalian epidermis, J. Lipid Res. 33 301-314, 1992. 

Structure of SC and its lipid content affect the permeability barrier function. Visualization studies revealed that the penetration route across the SC resides in the intercellular tortuous pathway between the corneocytes. This implies that SC lipids play a key role in the skin barrier function.27 Another major controlling element in barrier homeostasis seems to be the epidermal Calcium ion.28... 

Membranes are dynamic structures in which proteins float in a sea of lipids. The lipid components of the membrane form the permeability barrier, and protein components act as a transport system of pumps and channels that endow the membrane with selective permeability. 

Polymyxin E (colistin) is used in the treatment of serious Gram-negative bacterial infections, particularly those caused by Pseudomonas aeruginosa. It binds tightly to the lipid A component of LPS in the outer membrane of Gram-negative bacteria. The outer leaflet of the membrane structure is distorted, segments of which are released and the permeability barrier is destroyed. The polymyxin mole-... 

As the skin has evolved to impede the flux of toxins into the body and minimize water loss, it shows a very low permeability to the penetration of foreign molecules [169]. A unique hierarchical structure of lipid-rich matrix with embedded corneocyte in the upper strata (15 pm) of the skin—the stratum corneum (SC)—is essentially responsible for this barrier. The corneocytes, comprising cross-linked keratin fibers, are about 0.2-0.4 pm thick and about 40 pm wide [170]. They are held together by corneodesmosomes, which confer structural stability to the SC. The SC lipids are composed primarily of ceramides, cholesterol, and fatty acids that are assembled into multilamellar bilayers. This unusual extracellular matrix of lipid bilayers serves the primary barrier function of the SC. The layer of lipids immediately adjacent to each corneocyte is covalently bound to the corneocyte and is important in maintaining barrier function. The SC... 

Elias PM, Friend DS (1975) The permeability barrier in mammalian epidermis. J Cell Biol 65 180 Elias PM, Menon GK (1991) Structural an lipid biochemical correlates of the epidermal permeability barrier. Adv Lipid Res 24 1... 

All of these events can be ascribed to the release of constraints imposed on non-bilayer lipids to maintain them in a bilayer phase required to achieve a stable membrane structure. Exposure to high temperatures serves to phase separate the non-bilayer lipids into discrete domains that appear to be devoid of membrane proteins. It is likely also that the permeability barrier properties are altered by this type of phase separation. In general, where gross non-bilayer phase separations have taken place it is difficult to imagine how the normal distribution of membrane components can be achieved and especially at a rate that would be consistent with the continued survival of the cell. 

One of the key parameters for correlating molecular structure and chemical properties with bioavailability has been transcorneal flux or, alternatively, the corneal permeability coefficient. The epithelium has been modeled as a lipid barrier (possibly with a limited number of aqueous pores that, for this physical model, serve as the equivalent of the extracellular space in a more physiological description) and the stroma as an aqueous barrier (Fig. 11). The endothelium is very thin and porous compared with the epithelium [189] and often has been ignored in the analysis, although mathematically it can be included as part of the lipid barrier. Diffusion through bilayer membranes of various structures has been modeled for some time [202] and adapted to ophthalmic applications more recently [203,204]. For a series of molecules of similar size, it was shown that the permeability increases with octa-nol/water distribution (or partition) coefficient until a plateau is reached. Modeling of this type of data has led to the earlier statement that drugs need to be both... 

The importance of lipids in membrane structure was established early in the 20th century when pioneering biophysicists established positive correlations between cell membrane permeabilities to small non-electrolytes and the oil/water partition coefficients of these molecules. Contemporary measurements of the electrical impedance of cell suspensions suggested that cells are surrounded by a hydrocarbon barrier, which was first estimated to be about 3.3 nm thick. This was originally thought to be a lipid monolayer. Among the pioneering biophysical experiments were those that established that the ratio of the area of a monolayer formed from erythrocyte... 

---