Endothelial barriers

GPR4 SPC, LPC Migration, angiogenesis, impairment of endothelial barrier function... 

Brinkmann V, Cyster JG, Hla T (2004) FTY720 sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 4 1019-1025... 

In addition to the reports of uptake of intact small liposomes (SUV) by hepatocytes (Scherphof et al., 1983), there is some evidence of uptake of intravenously administered liposomes as intact structures by cells other than mononuclear phagocytes of the MPS. Recently, the integrity of the capillary endothelial barrier in several pathophysiological conditions was discussed (Bodor and Brewster, 1986). Several studies already indicated an increased capillary permeability during inflammation both in animals (Lopez-Berestein et al., 1984a) and in man (Morgan et al., 1985 Williams et al., 1987). 

Polymers, being macromolecules of considerable size and weight, have many limitations when used either as drugs or as drug carriers (1). One of the most serious limitations is the existence of epithelial or endothelial barriers (2). However, macromolecules can be transported by a vesicular process known as transcytosis (3,4). In transcytosis, a polymer can be shuttled across an epithelial cell by first... 

Soluble macromolecules permeate the endothelial barrier more readily than particulate macromolecules. The rate of movement of fluid across the endothelium appears to be directly related to the difference between the hydrostatic and osmotic forces. 

Figure 11.1 Ultrastructure of the human lung alveolar barrier. The tissue specimen is obtained via lung resection surgery. (A) Section through a septal wall of an alveolus. The wall is lined by a thin cellular layer formed by alveolar epithelial type I cells (ATI). Connective tissues (ct) separate ATI cells from the capillary endothelium (en) within which an erythrocyte (er) and granulocyte (gc) can be seen. The minimal distance between the alveolar airspace (ai) and erythrocyte is about 800-900 nm. The endothelial nucleus is denoted as n. (B) Details of the lung alveolar epithelial and endothelial barriers. Numerous caveolae (arrows) are seen in the apical and basal plasma membranes of an ATI cell as well as endothelial cell (en) membranes. Caveolae may partake transport of some solutes (e.g., albumin). (C) ATII cells (ATII) are often localised in the comers of alveoli where septal walls branch off. (D) ATII cells are characterised by numerous multilamellar bodies (mlb) which contain components of surfactant. A mitochondrion is denoted as mi.

With the use of isolated cells and functionally intact isolated brain capillaries, we certainly have the appropriate tools to study and to better understand the regulation and function of this important endothelial barrier. 

The FFA released by the adipocytes is collected by albumin and is transported to the various tissues in the blood. The albumin-FFA complex is able to cross the endothelial barrier in the capillaries and enter the interstitial space and so deliver this important fuel to the plasma membrane of the cell. To facilitate the transport of free fatty acids across the plasma membrane and within the cell, other transport proteins are present these are known as fatty acid binding proteins (FABP). 

Birukova, A. A., Adyshev, D., Gorshkov, B., Bokoch, G. M., Birukov, K. G., and Verin, A. D. (2006). GEF-H1 is involved in agonist-induced human pulmonary endothelial barrier dysfunction. Am.J. Physiol. LungCellMol. Physiol. 290, L540-L548. 

Warfel JM, Steele AD, D Agnillo F (2005) Anthrax lethal toxin induces endothelial barrier dysfunction. Am J Pathol 166 1871-1881... 

D-Ala-deltorphin-I and -II transverse the blood brain barrier in vivo and in vitro [51]. Recently, D-Ala-deltorphin-II was identified as a transport substrate of organic anion transporting polypeptides (Oatp/OATP), a family of polyspecific membrane transporters, strongly expressed at the rat and human blood brain barrier [52]. Modified analogues of these peptides were synthesized to improve their transit across the blood brain barrier [48,49,53]. Because they resist enzyme degradation and can cross endothelial barriers into the CNS, the deltorphins meet the criteria for peptides with potential for systemic administration. 

From Figure 1.3 it can be seen that in order to reach the underlying blood capillaries to be absorbed, the drug must pass through at least two epithelial membrane barriers (the apical and basolateral epithelial cell membranes) and also the endothelial membrane of the capillaries. In some cases, for example in stratified epithelia such as that found in the skin and buccal mucosa, the epithelial barrier comprises a number of cell layers rather than a single epithelial cell. Thus the effective barrier to drag absorption is not diffusion across a single membrane as described above, but diffusion across the entire epithelial and endothelial barrier, which may comprise several membranes and cells in series. 

Biodistribution of plasmid to either extracellular or intracellular targets is dependent on the structure of capillary walls, (patho)physiological conditions, the rate of blood and lymph supply, the physicochemical properties of plasmid and its carrier molecules. The fate of plasmid after in vivo administration is illustrated in Figure 14.4. The blood capillary walls are comprised of four layers, namely plasma-endothelial interface, endothelium, basal lamina, and adventia. Macromolecules can cross the endothelial barrier ... 

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