Colon epithelial permeability

Suzuki T, Yoshida S, Hara H. Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. BrJNutr. 2008 100 297-305. 

W Rubas, N Jezyk, GM Grass. Comparison of the permeability characteristics of a human colonic epithelial (Caco-2) cell line to colon of rabbit, monkey, and dog intestine and human drug absorption. Pharm Res 10 113-118, 1993. 

Borchardt. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability, Gastroenterology 1989, 96, 736—749... 

Another human colonic cancer cell line is T84, which forms monolayers that are even tighter than those of the Caco-2. It has been described as resembling a colonic crypt cell phenotype. Hence, these cells have been used mainly in studies of epithelial ion secretion and are generally not considered to be adequate for drug transport studies, particularly with respect to carrier-mediated processes [13, 91, 92]. The rat intestinal epithelial cell line IEC-18 has been evaluated as a model to study small intestinal epithelial permeability. This cell line, which forms very leaky monolayers, was proposed to be a better model than the Caco-2 monolayers for evaluating the small intestinal paracellular permeation of hydrophilic molecules [93]. Importantly, the leaky tight junctions of the IEC-18 cells are a result of an undeveloped paracellular barrier lacking the perijunctional actin belt. In addition, the IEC-18 cells have minute expression of transporters [91, 93]. 

Hidalgo IJ, Raub TJ, and Borchardt RT. Characterization of Human Colon Carcinoma Cell Line (Caco-2) as a Model System for Intestinal Epithelial Permeability. Gastroenterology 1989 96 736-749. 

Rubas W, J ezyk N, and Grass GM. Comparison of the Permeability Characteristics of a Human Colonic Epithelial (Caco-2) Cell Line to Colon of Rabbit, Monkey and Dog Intestine and Human Drug Absorption. PharmBes 1993 10 113—118. 

YPM-mediated immune activation may play a role in the pathophysiology of gut dysfunction observed during Y. pseudotuberculosis infection [41], In vitro, YPM was able to alter epithelial function by reducing active ion transport and increasing epithelial permeability. Interferon-y, interleukin-2, and tumour necrosis factor (TNF)-a were implicated in these processes. Colonic tissue from YPM-treated mice (20 p.g intraperitoneally) displayed reduced responsiveness to cAMP-mediated secretagogues and nerve stimulation. Immune activation by YPM in vivo was demonstrated by increased spleen cell proliferation and production of interleukin-2. 

The lanthaninn teehnique was used to study the epithelial permeability in the rat small intestine (Madara and Trier 1982). Dense lanthanum precipitates in TJ and paracellular spaces were restricted to a subpopulation of villous goblet cells and were not found between villous absorptive cells. These TJ were also permeable to barium, but not to macromolecular tracers such as microperoxidase, eytochrome c and horseradish peroxidase. It was also shown that palmitoylcamitine (PCC) opens TJ in a monolayer of Caco-2 colon carcinoma cells this phenomenon appears to be responsible for the significant enhancement of the absorption of hydrophilic drugs across intestinal mucosa caused by PCC and other long-chain acylcamitines (Hochman, Fix et al. 1994).In an experiment on rats, it was demonstrated that immobilisation stress induced a significant (but reversible) increase in epithelial permeability to the lanthanum tracer (Mazzon, Stumiolo et al. 2002). 

Another human colonic cancer cell line is T84 this develops monolayers of high TER ( 1000 Q cm2) when grown on permeable supports, but cells are not well differentiated and have been described as resembling a colonic crypt cell phenotype. Hence, these cells have been used mainly in studies of epithelial ion transport and are generally not considered to be adequate for drug transport studies, particularly with respect to carrier-mediated processes [10, 79, 82-84]. 

Other cell lines used in permeability studies include the T84 human colonic adenocarcinoma colonic crypt cell model. This line has a reduced carrier expression, secrets mucus, and has very high resistance [31, 32], The IEC cell line is a rat fetal intestinal epithelium cell with higher permeabilities than Caco-2 cells [33], LLC PKi is a pig kidney epithelial cell line with low expression of efflux systems, but expression systems for transport proteins [32], 2/4/A1 cells are a conditionally immortalized rat fetal intestinal epithelium line with crypt cell-like morphology and temperature-sensitive differentiation [34], They form differentiated monolayers with tight junctions, increased brush border enzymes when grown on extracellular matrices with laminin. Transport of drugs with LP in 2/4/A1 monolayers was comparable to that in the human jejunum and up to 300 times faster than that in Caco-2 monolayers. In contrast, the permeability of HP drugs was comparable in both cell lines [34],... 

Absorption barriers are related to the permeability of drug molecules across the gastrointestinal membrane including the colonic membrane. There are two distinct mechanisms for molecules to cross the membrane via paracellular transport and transcellular transport (Fig. 5). Para-cellular transport involves only passive diffusion where the molecules pass through the tight junctions between the epithelial cells. In contrast, transcellular transport can occur by passive diffusion as well as by active transport, or endocytosis. In general, the hydrophilic molecules diffuse predominantly through the paracellular route, whereas the lipophilic... 

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