The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens. Epithelial cells are linked together at the apical junctional complex by tight junctions that reduce the extracellular space and the passage of charge entities while forming a physical barrier to lipophilic molecules. Cultured intestinal epithelial cells have been extensively used to study intestinal absorption of newly synthesized drugs and the regulation of tight junctions structure and function. In vitro mild irritants, proinflammatory cytokines, toxins and pathogens, and adverse environmental conditions open tight junctions and increase paracellular permeability, an effect often accompanied by immune activation of the enterocytes. Conversely, inhibition of proinflammatory cytokines, exposure to growth factors and probiotics, among others, exert a protective effect. Impaired barrier function results from activation of signalling pathways that lead to alteration of junctional proteins expression and/or distribution. In vivo, intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection. This review will describe the current knowledge of the mechanisms regulating tight junctions and intestinal permeability, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are.

1 The pharmacological pro®le was studied of MEN 11420, or cyclo{[Asn(b-D-GlcNAc)-Asp-Trp-PheDap-Leu]cyclo(2b-5b)}, a glycosylated derivative of the potent, selective, conformationally-constrained tachykinin NK 2 receptor antagonist MEN 10627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2b-5b)). and ion channels. 4 In the rabbit isolated pulmonary artery and rat urinary bladder MEN 11420 potently and competitively antagonized tachykinin NK 2 receptor-mediated contractions (pK B =8.6+0.07, n=10, and 9.0+0.04, n=12; Schild plot slope=71.06 (95% c.l.=71.3; 70.8) and 71.17 (95% c.l.=71.3; 71.0), respectively). MEN 11420 produced an insurmountable antagonism at NK 2 receptors in the hamster trachea and mouse urinary bladder. However, in both preparations, the eect of MEN 11420 was reverted by washout and an apparent pK B of 10.2+0.14, n= 9, and 9.8+0.15, n=9, was calculated in the hamster trachea and mouse urinary bladder, respectively. 5 MEN 11420 showed low anity (pK B 56) at guinea-pig and rat tachykinin NK 1 (guinea-pig ileum and rat urinary bladder) and NK 3 (guinea-pig ileum and rat portal vein) receptors. On the whole, the anities (potency and selectivity) showed by MEN 11420 for dierent tachykinin receptors, measured either in binding or in functional bioassays, were similar to those shown by the parent compound, MEN 10627. ) and intraduodenal (100 ± 300 nmol kg 71 ) administration of MEN 11420. MEN 11420 was more potent (about 10 fold) and longer lasting than its parent compound MEN 10627, possibly due to a greater metabolic stability. 7 A dose of MEN 11420 (100 nmol kg 71 , i.v.), that produced potent and long lasting inhibition of the contraction of the rat urinary bladder induced by challenge with the NK 2 selective receptor agonist [bAla 8 ]neurokinin A(4 ± 10) (10 ± 300 nmol kg 71 ), was without eect on the responses produced by the NK 1 receptor selective agonist [Sar 9 ]substance P sulphone (1 ± 10 nmol kg 71 ). 8 These ®ndings indicate that MEN 11420 is a potent and selective tachykinin NK 2 receptor antagonist. The introduction of a sugar moiety did not produce major changes in the anity pro®le of this antagonist as compared to MEN 10627, but markedly improved its in vivo potency and duration of action. With these characteristics, MEN 11420 is a suitable candidate for studying the pathophysiological signi®cance of tachykinin NK 2 receptors in humans.

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