Journal articles on the topic 'Epithelial permeability'
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1
Maharshak, Nitsan, Eun Young Huh, Chorlada Paiboonrungruang, Michael Shanahan, Lance Thurlow, Jeremy Herzog, Zorka Djukic, et al. "Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2." Infection and Immunity 83, no. 7 (April 27, 2015): 2762–70. http://dx.doi.org/10.1128/iai.00425-15.
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Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbeEnterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) fromE. faecalisV583 andE. faecalislacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutantE. faecalisstrains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2−/−) mice were used to investigate the role of this receptor inE. faecalis-induced permeability. Gelatinase (GelE) purified fromE. faecalisV583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2−/−mice by fecal supernatants from ulcerative colitis patients was assessed. SecretedE. faecalisproteins induced permeability in epithelial cell monolayers, which was reduced in the absence ofgelEor by blocking PAR2 activity. SecretedE. faecalisproteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2−/−mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2−/−mice. Our investigations demonstrate that GelE fromE. faecaliscan regulate enteric epithelial permeability via PAR2.
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Lewis, S. A., J. R. Berg, and T. J. Kleine. "Modulation of epithelial permeability by extracellular macromolecules." Physiological Reviews 75, no. 3 (July 1, 1995): 561–89. http://dx.doi.org/10.1152/physrev.1995.75.3.561.
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Epithelia are sheets of cells joined together by tight junctions. This geometry allows an epithelium to act as a barrier, i.e., restrict the movement of substances between two compartments that it separates (typically 1 compartment is the blood) and also to actively and selectively transport substances between the two compartments. It has been known for a number of years that both the barrier and transport functions of epithelia can be regulated by hormones and neurotransmitters, and this regulation is a central component of plasma electrolyte and nonelectrolyte homeostasis. Less appreciated is that these epithelial functions can be modified by macromolecules other than neurotransmitters and hormones. These macromolecules have been divided into the following categories: proteases, cytokines, cellular constituents, nonbacterial xenobiotics, and bacterial xenobiotics. Such macromolecules can alter epithelial transport and barrier function by a number of different mechanisms. These include proteolysis of epithelial ion channels and tight junctional complexes, conversion of an ion pump into a nonselective cation channel, increase in epithelial membrane permeability resulting in cell swelling and lysis, and up- or downregulation of cellular second messenger systems that can alter ion transport capabilities or prove cytotoxic to the cells. Finally, these modifications can be either transient or chronic in nature and in many circumstances result in a perturbation of the electrolyte and nonelectrolyte status of the host organism.
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Negrete, H. O., J. P. Lavelle, J. Berg, S. A. Lewis, and M. L. Zeidel. "Permeability properties of the intact mammalian bladder epithelium." American Journal of Physiology-Renal Physiology 271, no. 4 (October 1, 1996): F886—F894. http://dx.doi.org/10.1152/ajprenal.1996.271.4.f886.
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Because the mammalian bladder must store urine of composition which differs markedly from that of plasma for prolonged periods, the bladder permeability barrier must maintain extremely low permeabilities to substances which normally cross membranes relatively rapidly, such as water, protons, and small nonelectrolytes like urea and ammonia. In the present studies, permeabilities of the apical membrane of dissected rabbit bladder epithelium to water, urea, ammonia, and protons were measured in Ussing chambers and averaged (in cm/s) for water, 5.15 +/- 0.43 x 10(-5); for urea, 4.51 +/- 0.67 x 10(-6); for ammonia, 5.14 +/- 0.62 x 10(-4); and for protons, 2.98 +/- 1.87 x 10(-3), respectively. These permeability values are exceptionally low and are expected to result in minimal to no leakage of these normally permeable substances across the epithelium. Water permeabilities in intact whole rabbit bladders were indistinguishable from those obtained in the dissected epithelial preparation. Moreover, addition of nystatin to the apical solution of dissected epithelia rapidly increased water permeability in conjunction with loss of epithelial resistance. These results confirm that the apical membrane of the bladder epithelial cells represents the bladder permeability barrier. In addition, they establish a model system that will permit examination of how membrane structure reduces permeability and how epithelial injury compromises barrier function.
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Ludwigs, Ulf, Anders Philip, Bengt Robertson, and Göran Hedenstierna. "Pulmonary Epithelial Permeability." Chest 110, no. 2 (August 1996): 486–93. http://dx.doi.org/10.1378/chest.110.2.486.
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LANGFORD, J. A., C. A. LEWIS, A. R. GELLERT, S. E. J. TOLFREE, and R. M. RUDD. "Pulmonary epithelial permeability." Nuclear Medicine Communications 7, no. 3 (March 1986): 183–90. http://dx.doi.org/10.1097/00006231-198603000-00006.
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Peterson, Michael W., and Jennifer Kirschbaum. "Asbestos-induced lung epithelial permeability: potential role of nonoxidant pathways." American Journal of Physiology-Lung Cellular and Molecular Physiology 275, no. 2 (August 1, 1998): L262—L268. http://dx.doi.org/10.1152/ajplung.1998.275.2.l262.
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Asbestos fibers are an important cause of lung fibrosis; however, the biological mechanisms are incompletely understood. The lung epithelium serves an important barrier function in the lung, and disrupting the epithelial barrier can contribute to lung fibrosis. Lung epithelial permeability is increased in patients with asbestosis, and asbestos fibers increase permeability across cultured human lung epithelium. However, the mechanism of this increased permeability is not known. Many of the biological effects of asbestos are postulated to be due to its ability to generate oxidants, and oxidants are known to increase epithelial permeability. However, we previously reported that altering the iron content of asbestos (important in oxidant generation) had no effect on its ability to increase permeability. For that reason, we undertook these studies to determine whether asbestos increases epithelial permeability through nonoxidant pathways. Both extracellular (H2O2) and intracellular (menadione) oxidants increase paracellular permeability across human lung epithelial monolayers. Extracellular catalase but not superoxide dismutase prevented increased permeability after both oxidant exposures. However, catalase offered no protection from asbestos-induced permeability. We next depleted the cells of glutathione or catalase to determine whether depleting normal cellular antioxidants would increase the sensitivity to asbestos. Permeability was the same in control cells and in cells depleted of these antioxidants. In addition to generating oxidants, asbestos also activates signal transduction pathways. Blocking protein kinase C activation did not prevent asbestos-induced permeability; however, blocking tyrosine kinase with tyrophostin A25 did prevent asbestos-induced permeability, and blocking tyrosine phosphatase with sodium vanadate enhanced the effect of asbestos. These data demonstrate that asbestos may increase epithelial permeability through nonoxidant pathways that involve tyrosine kinase activation. This model offers an important system for studying pathways involved in regulating lung epithelial permeability.
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Pinker, Elisha, and Timur Tuganbaev. "Microbiome Composition and Circadian Rhythm Disruption Alters Epithelial Barrier Integrity." Columbia Undergraduate Science Journal 15 (May 24, 2021): 6–15. http://dx.doi.org/10.52214/cusj.v15i1.7408.
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The intestine is home to one of the most complex ecological communities, termed the human gut microbiome. The gut microbiome modulates a wide range of human diseases from diabetes to neurological disorders to cancer. Separating the host and the gut microbiome is the epithelial barrier. The intestinal epithelium serves as an adaptive interaction hub between the host and microbiome that plays an important role in deciding the outcome of host-microbiome interactions. Regulation of epithelial barrier permeability to ions, nutrients and microbiome metabolites is known to be a tightly controlled process on the host side. However, whether the microbiome community also affects epithelial permeability remains unclear. Here, we show that alterations in microbiota composition by treatment with antibiotics selectively targeting specific members of the microbiome community impacts the permeability of the intestine. Additionally, modulating the microbiome through other methods such as altering diet composition shows changes in permeability of the epithelial barrier. As daily feeding rhythm entrains diurnal fluctuations in microbiome, we have set out to measure epithelial barrier permeability throw out the clock. We have discovered that the permeability of the intestinal epithelial barrier exhibits circadian rhythms in mice. Disruption of these rhythms, through jet-lag or genetic deficiencies in circadian machinery, consequently alters epithelial barrier integrity. Together, these findings provide evidence that disruptions in circadian rhythms as well as alterations in microbiome composition have direct consequences in intestinal permeability, and that microbiome might serve as a tool in regulating epithelium permeability.
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Merchant, R. K., M. W. Peterson, and G. W. Hunninghake. "Silica directly increases permeability of alveolar epithelial cells." Journal of Applied Physiology 68, no. 4 (April 1, 1990): 1354–59. http://dx.doi.org/10.1152/jappl.1990.68.4.1354.
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Alveolar epithelial cell injury and increased alveolar-capillary membrane permeability are important features of acute silicosis. To determine whether silica particles contribute directly to this increased permeability, we measured paracellular permeability of rat alveolar epithelium after exposure to silica, in vitro, using markers of the extracellular space. Silica (Minusil) markedly increased permeability in a dose- and time-dependent manner. This was not the result of cytolytic injury, because lactate dehydrogenase release from monolayers exposed to silica was not increased. Pretreatment of the silica with serum, charged dextrans, or aluminum sulfate blocked the increase in permeability. Scanning electron microscopy demonstrated adherence of the silica to the surface of the alveolar epithelial cells. Thus silica can directly increase permeability of alveolar epithelium.
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Moseley, P. L., C. Gapen, E. S. Wallen, M. E. Walter, and M. W. Peterson. "Thermal stress induces epithelial permeability." American Journal of Physiology-Cell Physiology 267, no. 2 (August 1, 1994): C425—C434. http://dx.doi.org/10.1152/ajpcell.1994.267.2.c425.
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The mechanisms by which heat injury results in multiorgan system failure are unknown, but the presence of endotoxemia and intestinal hemorrhage suggests that changes in gut epithelial permeability may be crucial to this process. To determine whether alterations in epithelial permeability occur at physiologically relevant temperatures, heat-induced changes on epithelial barrier integrity were studied using a high-resistance clone of Madin-Darby canine kidney epithelial cells. Transepithelial electrical conductance increased when monolayers were heated above 38.3 degrees C. Early changes in conductance were completely reversible with cooling. Increased conductance was due to increased paracellular permeability because heat also induced increased mannitol permeability across the monolayers. A conditioning heat stress (42 degrees C for 90 min) altered heat-induced permeability. When cell monolayers were exposed to this conditioning stress 48 h before measurement of conductance with increasing temperatures, the conductance increase did not occur until they were heated to 39.4 degrees C compared with 38.8 degrees C in naive control cells. This conditioning treatment also conferred thermotolerance as measured by cell survival after a lethal 45.0 degrees C heat stress. There was no difference in the temperature at which conductance increased between preheated and control cells 96 h after a preconditioning heat stress. The conditioning heat stress resulted in accumulation of heat-shock protein (HSP) 70 in cells at 48 h, but HSP 70 returned to control levels at 96 h. These studies demonstrate that small temperature elevations increase epithelial permeability and that prior heat stress which induces HSP 70 shifts the threshold temperature required to disrupt the epithelium.
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Min, Hyun Jin, Tae Hoon Kim, Joo-Heon Yoon, and Chang-Hoon Kim. "Hypoxia Increases Epithelial Permeability in Human Nasal Epithelia." Yonsei Medical Journal 56, no. 3 (2015): 825. http://dx.doi.org/10.3349/ymj.2015.56.3.825.
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Chung, Hyo Jin, Hyun Jin Min, Da Hee Kim, and Chang-Hoon Kim. "Hypoxia Increases Epithelial Permeability in Human Nasal Epithelia." Otolaryngology–Head and Neck Surgery 151, no. 1_suppl (September 2014): P120—P121. http://dx.doi.org/10.1177/0194599814541627a286.
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Allam-Ndoul, Bénédicte, Sophie Castonguay-Paradis, and Alain Veilleux. "Gut Microbiota and Intestinal Trans-Epithelial Permeability." International Journal of Molecular Sciences 21, no. 17 (September 3, 2020): 6402. http://dx.doi.org/10.3390/ijms21176402.
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Constant remodeling of tight junctions to regulate trans-epithelial permeability is essential in maintaining intestinal barrier functions and thus preventing diffusion of small molecules and bacteria to host systemic circulation. Gut microbiota dysbiosis and dysfunctional gut barrier have been correlated to a large number of diseases such as obesity, type 2 diabetes and inflammatory bowel disease. This led to the hypothesis that gut bacteria-epithelial cell interactions are key regulators of epithelial permeability through the modulation of tight junctions. Nevertheless, the molecular basis of host-pathogen interactions remains unclear mostly due to the inability of most in vitro models to recreate the differentiated tissue structure and components observed in the normal intestinal epithelium. Recent advances have led to the development of a novel cellular model derived from intestinal epithelial stem cells, the so-called organoids, encompassing all epithelial cell types and reproducing physiological properties of the intestinal tissue. We summarize herein knowledge on molecular aspects of intestinal barrier functions and the involvement of gut bacteria-epithelial cell interactions. This review also focuses on epithelial organoids as a promising model for epithelial barrier functions to study molecular aspects of gut microbiota-host interaction.
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O'Brodovich, Hugh. "On pulmonary epithelial permeability." Pediatric Pulmonology 1, no. 5 (September 1985): 291. http://dx.doi.org/10.1002/ppul.1950010534.
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Felwick, Richard K., Geraint J. R. Dingley, Rocio Martinez-Nunez, Tilman Sanchez-Elsner, J. R. Fraser Cummings, and Jane E. Collins. "MicroRNA23a Overexpression in Crohn’s Disease Targets Tumour Necrosis Factor Alpha Inhibitor Protein 3, Increasing Sensitivity to TNF and Modifying the Epithelial Barrier." Journal of Crohn's and Colitis 14, no. 3 (October 18, 2019): 381–92. http://dx.doi.org/10.1093/ecco-jcc/jjz145.
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Abstract Background and Aims Mucosal healing is important in Crohn’s disease therapies. Epithelial homeostasis becomes dysregulated in Crohn’s, with increased permeability, inflammation, and diarrhoea. MicroRNAs are small non-coding RNAs that regulate gene expression and show changes in inflammatory bowel disease. Tumour necrosis factor alpha [TNFα] inhibitor protein 3 is raised in Crohn’s and regulates TNFα-mediated activation of NFκB. We investigated TNFα regulation by microRNA in Crohn’s disease [CD], and studied effects on epithelial permeability and inflammation. Methods Colonic epithelium from CD and healthy donor biopsies was isolated using laser capture microdissection, and microRNA was quantified. Tumour necrosis factor alpha inhibitor protein 3 was characterised immunohistochemically on serial sections. Expression effect of microRNA was confirmed with luciferase reporter assays. Functional barrier permeability studies and innate cytokine release were investigated with cell and explant culture studies. Results MicroRNA23a levels significantly increased in colonic Crohn’s epithelium compared with healthy epithelium. Luciferase reporter assays in transfected epithelial cells confirmed that microRNA23a repressed expression via the 3’ untranslated region of tumour necrosis factor alpha inhibitor protein 3 mRNA, coinciding with increased NFκB-mediated transcription. Immunohistochemical staining of TNFAIP3 protein in colonic biopsies was reduced or absent in adjacent Crohn’s sections, correlating inversely with microRNA23a levels and encompassing some intercohort variation. Overexpression of microRNA23a increased epithelial barrier permeability in a colonic epithelial model and increased inflammatory cytokine release in cultured explant biopsies, mimicking Crohn’s disease characteristics. Conclusions MicroRNA23a overexpression in colonic Crohn’s epithelium represses tumour necrosis factor alpha inhibitor protein 3, enhancing sensitivity to TNFα, with increased intestinal permeability and cytokine release.
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McKay, Catherine M., and Derek M. McKay. "Control the Epithelial Barrier: A Pivotal First Line of Defense." Canadian Journal of Gastroenterology 18, no. 2 (2004): 119–20. http://dx.doi.org/10.1155/2004/215359.
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Lumen-derived material gains access to the mucosa by permeating between adjacent epithelial cells (ie, paracellular pathway), by transcytosis across the apical and basolateral cell membranes (ie, transcellular pathway) or by exploiting breaks or erosions in the epithelium that may, for example, result from inflammation. Increased epithelial permeability (or decreased barrier function) has repeatedly been demonstrated in a variety of gut disturbances; notably, in inflammatory bowel disease (IBD). There has been an exponential increase in our knowledge of the structural elements that comprise the epithelial barrier, and of the intrinsic factors (eg, cytokines) and external stimuli (eg, bacterial toxins) that can either perturb or enhance epithelial permeability. Canadian researchers have been very active in the study of epithelial permeability and have been responsible for major advances in the field, documenting increased permeability in patients with ulcer disease and IBD and some of their first degree relatives (as well as before onset of overt inflammation), and elucidating mechanisms of stress-induced and cytokine-induced increases in permeability (1-8). A recent study from Scott et al (9) continues this impressive tradition.
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Zabner, Joseph, Michael Winter, Katherine J. D. Ashbourne Excoffon, David Stoltz, Dana Ries, Sandra Shasby, and Michael Shasby. "Histamine alters E-cadherin cell adhesion to increase human airway epithelial permeability." Journal of Applied Physiology 95, no. 1 (July 2003): 394–401. http://dx.doi.org/10.1152/japplphysiol.01134.2002.
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During the immediate response to an inhaled allergen, there is an increase in the paracellular permeability of the airway epithelium.1Histamine is an important agonist released during the immediate response to inhaled allergen. We hypothesized that histamine would increase human airway epithelial paracellular permeability and that it would do this by interrupting E-cadherin-based cell adhesion. Histamine, applied to the basolateral surface, increased the paracellular permeability of cultured human airway epithelia, and this effect of histamine was blocked by the histamine receptor antagonist promethazine. ECV304 cells express a histamine receptor, N-cadherin, and elements of the tight junction, including claudins, but they do not express E-cadherin. Histamine increased the paracellular permeability of ECV304 cells transfected with a vector and expressing E-cadherin but not ECV304 cells expressing lac-Z in the same vector. L cells do not express the histamine receptor, cadherins, or claudins. Histamine decreased adhesion of L cells expressing the human histamine receptor and E-cadherin to an E-cadherin-Fc fusion protein. Histamine did not alter the adhesion to the E-cadherin fusion protein of L cells expressing either the histamine receptor or E-cadherin alone. When applied to the apical surface, adenovirus poorly infects airway epithelial cells because its receptor, CAR, is restricted to the basolateral surface of the cells. When histamine was applied to the basolateral surface of airway epithelial cells, infection of the cells by adenovirus increased by approximately one log. This effect of histamine was also blocked by promethazine. Histamine increases airway paracellular permeability and increases susceptibility of airway epithelial cells to infection by adenovirus by interrupting E-cadherin adhesion.
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Ayala-Torres, Carlos, Susanne M. Krug, Rita Rosenthal, and Michael Fromm. "Angulin-1 (LSR) Affects Paracellular Water Transport, However Only in Tight Epithelial Cells." International Journal of Molecular Sciences 22, no. 15 (July 22, 2021): 7827. http://dx.doi.org/10.3390/ijms22157827.
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Water transport in epithelia occurs transcellularly (aquaporins) and paracellularly (claudin-2, claudin-15). Recently, we showed that downregulated tricellulin, a protein of the tricellular tight junction (tTJ, the site where three epithelial cells meet), increased transepithelial water flux. We now check the hypothesis that another tTJ-associated protein, angulin-1 (alias lipolysis-stimulated lipoprotein receptor, LSR) is a direct negative actuator of tTJ water permeability depending on the tightness of the epithelium. For this, a tight and an intermediate-tight epithelial cell line, MDCK C7 and HT-29/B6, were stably transfected with CRISPR/Cas9 and single-guide RNA targeting angulin-1 and morphologically and functionally characterized. Water flux induced by an osmotic gradient using 4-kDa dextran caused water flux to increase in angulin-1 KO clones in MDCK C7 cells, but not in HT-29/B6 cells. In addition, we found that water permeability in HT-29/B6 cells was not modified after either angulin-1 knockout or tricellulin knockdown, which may be related to the presence of other pathways, which reduce the impact of the tTJ pathway. In conclusion, modulation of the tTJ by knockout or knockdown of tTJ proteins affects ion and macromolecule permeability in tight and intermediate-tight epithelial cell lines, while the transepithelial water permeability was affected only in tight cell lines.
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al-Nakkash, L., and C. U. Cotton. "Bovine pancreatic duct cells express cAMP- and Ca(2+)-activated apical membrane Cl- conductances." American Journal of Physiology-Gastrointestinal and Liver Physiology 273, no. 1 (July 1, 1997): G204—G216. http://dx.doi.org/10.1152/ajpgi.1997.273.1.g204.
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Secretion of salt and water by the epithelial cells that line pancreatic ducts depends on activation of apical membrane Cl- conductance. In the present study, we characterized two types of Cl- conductances present in the apical cell membrane of bovine pancreatic duct epithelial cells. Primary cultures of bovine main pancreatic duct epithelium and an immortalized cell line (BPD1) derived from primary cultures were used. Elevation of intracellular adenosine 3',5'-cyclic monophosphate (cAMP) or Ca2+ in intact monolayers of duct epithelium induced sustained anion secretion. Agonist-induced changes in plasma membrane Cl- permeability were accessed by 36 Cl- efflux, whole cell current recording, and measurements of transepithelial Cl- current across permeabilized epithelial monolayers. Elevation of intracellular cAMP elicited a sustained increase in Cl- permeability, whereas elevation of intracellular Ca2+ induced only a transient increase in Cl- permeability. Ca(2+)- but not cAMP-induced increases in Cl- permeability were abolished by preincubation of cells with the Ca2+ buffer 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl) ester (BAPTA-AM). N-phenylanthranilic acid (DPC; 1 mM) and glibenclamide (100 microM), but not 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; 500 microM), inhibited the cAMP-induced increase in Cl- permeability. In contrast, DPC and DIDS, but not glibenclamide, inhibited the Ca(2+)-induced increase in Cl- permeability. We conclude from these experiments that bovine pancreatic duct epithelial cells express at least two types of Cl- channels, cAMP and Ca2+ activated, in the apical cell membrane. Because the Ca(2+)-activated increase in Cl- permeability is transient, the extent to which this pathway contributes to sustained anion secretion by the ductal epithelium remains to be determined.
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Canny, Geraldine, Elke Cario, Andreas Lennartsson, Urban Gullberg, Ciara Brennan, Ofer Levy, and Sean P. Colgan. "Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 3 (March 2006): G557—G567. http://dx.doi.org/10.1152/ajpgi.00347.2005.
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Epithelial cells of many mucosal organs have adapted to coexist with microbes and microbial products. In general, most studies suggest that epithelial cells benefit from interactions with commensal microorganisms present at the lumenal surface. However, potentially injurious molecules found in this microenvironment also have the capacity to elicit local inflammatory responses and even systemic disease. We have recently demonstrated that epithelia cells express the anti-infective molecule bactericidal/permeability-increasing protein (BPI). Here, we extend these findings to examine molecular mechanisms of intestinal epithelial cell (IEC) BPI expression and function. Initial experiments revealed a variance of BPI mRNA and protein expression among various IEC lines. Studies of BPI promoter expression in IECs identified regulatory regions of the BPI promoter and revealed a prominent role for CCAAT/enhancer binding protein and especially Sp1/Sp3 in the basal regulation of BPI. To assess the functional significance of this protein, we generated an IEC line stably transfected with full-length BPI. We demonstrated that, whereas epithelia express markedly less BPI protein than neutrophils, epithelial BPI contributes significantly to bacterial killing and attenuating bacterial-elicted proinflammatory signals. Additional studies in murine tissue ex vivo revealed that BPI is diffusely expressed along the crypt-villous axis and that epithelial BPI levels decrease along the length of the intestine. Taken together, these data confirm the transcriptional regulation of BPI in intestinal epithelia and provide insight into the relevance of BPI as an anti-infective molecule at intestinal surfaces.
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Watson, James L., Sara Ansari, Heather Cameron, Arthur Wang, Mahmood Akhtar, and Derek M. McKay. "Green tea polyphenol (−)-epigallocatechin gallate blocks epithelial barrier dysfunction provoked by IFN-γ but not by IL-4." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 5 (November 2004): G954—G961. http://dx.doi.org/10.1152/ajpgi.00302.2003.
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A characteristic of many enteropathies is increased epithelial permeability, a potentially pathophysiological event that can be evoked by T helper (Th)-1 (i.e., IFN-γ) and Th2 (i.e., IL-4) cytokines and bacterial infection [e.g., enteropathogenic Escherichia coli (EPEC)]. The green tea polyphenol (−)-epigallocatechin gallate (EGCG) has immunosuppressive properties, and we hypothesized that it would ameliorate the increased epithelial permeability induced by IFN-γ, IL-4, and/or EPEC. EGCG, but not the related epigallocatechin, completely prevented the increase in epithelial (i.e., T84 cell monolayer) permeability caused by IFN-γ exposure as gauged by transepithelial resistance and horseradish peroxidase flux; EGCG did not alleviate the barrier disruption induced by IL-4 or EPEC. IFN-γ-treated T84 and THP-1 (monocytic cell line) cells displayed STAT1 activation (tyrosine phosphorylation on Western blot analysis, DNA binding on EMSA) and upregulation of interferon response factor-1 mRNA, a STAT1-dependent gene. All three events were inhibited by EGCG pretreatment. Aurintricarboxylic acid also blocked IFN-γ-induced STAT1 activation, but it did not prevent the increase in epithelial permeability. Additionally, pharmacological blockade of MAPK signaling did not affect IFN-γ-induced epithelial barrier dysfunction. Thus, as a potential adjunct anti-inflammatory agent, EGCG can block STAT1-dependent events in gut epithelia and monocytes and prevent IFN-γ-induced increased epithelial permeability. The latter event is both a STAT1- and MAPK-independent event.
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Lavelle, J. P., H. O. Negrete, P. A. Poland, C. L. Kinlough, S. D. Meyers, R. P. Hughey, and M. L. Zeidel. "Low permeabilities of MDCK cell monolayers: a model barrier epithelium." American Journal of Physiology-Renal Physiology 273, no. 1 (July 1, 1997): F67—F75. http://dx.doi.org/10.1152/ajprenal.1997.273.1.f67.
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Barrier epithelia such as the renal collecting duct (in the absence of antidiuretic hormone) and thick ascending limb, as well as the stomach and mammalian bladder, exhibit extremely low permeabilities to water and small nonelectrolytes. A cell culture model of such epithelia is needed to determine how the structure of barrier apical membranes reduce permeability and how such membranes may be generated and maintained. In the present studies, the transepithelial electrical resistance and isotopic water and urea fluxes were measured for Madin-Darby canine kidney (MDCK) type I and type II cells, as well as type I cells expressing the mucin protein, MUC1, in their apical membranes. Although earlier studies had found the unstirred layer effects too great to permit measurement of transepithelial permeabilities, use of ultrathin semipermeable supports in this study overcame this difficulty. Apical membrane diffusive water permeabilities were 1.8 +/- 0.4 x 10(-4) cm/s and 3.5 +/- 0.5 x 10(-4) cm/s in MDCK type I and type II cells, respectively, at 20 degrees C. Urea permeability in type I cells at the same temperature was 6.0 +/- 0.9 x 10(-6) cm/s. These values resemble those of other barrier epithelial apical membranes, either isolated or in intact epithelia, and the water permeability values are far below those of other epithelial cells in culture. Transfection of MDCK type I cells with the major human urinary epithelial mucin, MUC1, led to abundant expression of the fully glycosylated form of the protein on immunoblots, and flow cytometry revealed that virtually all the cells expressed the protein. However, MUC1 had no effect on water or urea permeabilities. In conclusion, MDCK cells grown on semipermeable supports form a model barrier epithelium. Abundant expression of mucins does not alter the permeability properties of these cells.
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Levy, O., G. Canny, C. N. Serhan, and S. P. Colgan. "Expression of BPI (bactericidal/permeability-increasing protein) in human mucosal epithelia." Biochemical Society Transactions 31, no. 4 (August 1, 2003): 795–800. http://dx.doi.org/10.1042/bst0310795.
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Among the antimicrobial proteins and peptides of humans is the cationic 55 kDa bactericidal/permeability-increasing protein (BPI), which possesses antibacterial, endotoxin-neutalizing and opsonic activity against Gram-negative bacteria. Although identified originally as an abundant constituent of neutrophil granules, we have recently identified functional expression of BPI by human mucosal epithelia. BPI expression was markedly up-regulated by exposure of epithelia to lipoxins, endogenous anti-inflammatory eicosanoids that are generated in vivo in the context of aspirin treatment (aspirin-triggered lipoxins). Epithelial BPI was found to be surface expressed and fully functional, as measured by antibacterial activity against Salmonella typhimurium as well as lipopolysaccharide (LPS; endotoxin)-neutralizing activity. These results suggest a role for BPI as an effector of epithelial antibacterial activity and as a modulator of epithelial responses to LPS. Both BPI and the lipoxins are currently the subject of intensive biopharmaceutical development, raising the possibility that therapeutic use of BPI or modulation of epithelial BPI expression may be a useful adjunctive therapy for conditions in which epithelial inflammation is associated with Gram-negative infections and/or endotoxin.
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Balkovetz, Daniel F. "Claudins at the gate: determinants of renal epithelial tight junction paracellular permeability." American Journal of Physiology-Renal Physiology 290, no. 3 (March 2006): F572—F579. http://dx.doi.org/10.1152/ajprenal.00135.2005.
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The epithelial tight junction (TJ) is responsible for the control of paracellular transport between epithelial cells (gate function) and the maintenance of apical/basolateral polarity by preventing the diffusion of membrane lipids and/or proteins from one surface domain to another (fence function). Renal tubule epithelia in the mammalian nephron have TJs that determine paracellular transport characteristics. Paracellular transport across renal tubular epithelial TJs (gate function) varies in different segments of the nephron. A large family of recently identified TJ-associated transmembrane proteins named claudins appear to determine the paracellular permeability properties of the TJ. A combination of inherited human diseases, renal epithelial cell culture models, and nephron expression patterns of claudins is providing important clues about how claudin molecules determine the TJ gate function of renal epithelia in different segments of the nephron.
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Wangensteen, O. D., L. A. Schneider, S. C. Fahrenkrug, G. M. Brottman, and R. C. Maynard. "Tracheal epithelial permeability to nonelectrolytes: species differences." Journal of Applied Physiology 75, no. 2 (August 1, 1993): 1009–18. http://dx.doi.org/10.1152/jappl.1993.75.2.1009.
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We developed a new excised tracheal preparation to measure the epithelial permeability of large lipid-insoluble nonelectrolytes and macromolecules. Tracheae were suspended vertically in a Ringer solution bath, and a solution containing labeled test solutes was positioned in the center of the tracheal segment, away from damaged ends. Permeability coefficients, calculated from solute fluxes into the bath, were constant for > or = 2 h at 37 degrees C, and no histological changes were observed. Measurements after epithelial removal with detergent indicate that in the intact trachea the epithelium represents > 90% of the resistance to transport. For the rat trachea, permeability coefficients for sucrose, inulin, and Dextran 20 were 9.22, 2.20, and 0.214 x 10(-7) cm/s, respectively. Values for cat tracheae were similar, those for rabbit tracheae were lower, and those for guinea pig tracheae were markedly greater. With the assumption of transport by diffusion through thin rectangular slits between epithelial cells, the rat and guinea pig data fit a slit width of 7–8 nm, whereas the rabbit and cat data cannot be explained by a model with slits of a single size.
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Bao, Shenying, and Daren L. Knoell. "Zinc modulates cytokine-induced lung epithelial cell barrier permeability." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 6 (December 2006): L1132—L1141. http://dx.doi.org/10.1152/ajplung.00207.2006.
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Apoptosis plays a causative role in acute lung injury in part due to epithelial cell loss. We recently reported that zinc protects the lung epithelium during inflammatory stress whereas depletion of intracellular zinc enhances extrinsic apoptosis. In this investigation, we evaluated the relationship between zinc, caspase-3, and cell-to-cell contact via proteins that form the adherens junction complex. Cell adhesion proteins are directly responsible for formation of the mechanical barrier of the lung epithelium. We hypothesized that exposure to inflammatory cytokines, in conjunction with zinc deprivation, would induce caspase-3, leading to degradation of junction proteins, loss of cell-to-cell contact, and compromised barrier function. Primary human upper airway and type I/II alveolar epithelial cultures were obtained from multiple donors and exposed to inflammatory stimuli that provoke extrinsic apoptosis in addition to depletion of intracellular zinc. We observed that zinc deprivation combined with tumor necrosis factor-α, interferon-γ, and Fas receptor ligation accelerates caspase-3 activation, proteolysis of E-cadherin and β-catenin, and cellular apoptosis, leading to increased paracellular leak across monolayers of both upper airway and alveolar lung epithelial cultures. Zinc supplementation inhibited apoptosis and paracellular leak, whereas caspase inhibition was less effective. We conclude that zinc is a vital factor in the lung epithelium that protects against death receptor-mediated apoptosis and barrier dysfunction. Furthermore, our findings suggest that although caspase-3 inhibition reduces lung epithelial apoptosis it does not prevent mechanical dysfunction. These findings facilitate future studies aimed at developing therapeutic strategies to prevent acute lung injury.
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LI, XIAO YANG, KENNETH DONALDSON, and WILLIAM MacNEE. "Lipopolysaccharide-induced Alveolar Epithelial Permeability." American Journal of Respiratory and Critical Care Medicine 157, no. 4 (April 1998): 1027–33. http://dx.doi.org/10.1164/ajrccm.157.4.9605080.
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Chan, T. B., J. P. Arm, J. Anderson, and N. M. Eiser. "Pulmonary epithelial permeability in bronchiectasis." British Journal of Diseases of the Chest 82 (January 1988): 56–63. http://dx.doi.org/10.1016/0007-0971(88)90008-3.
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Cavanaugh, Kenneth J., Taylor S. Cohen, and Susan S. Margulies. "Stretch increases alveolar epithelial permeability to uncharged micromolecules." American Journal of Physiology-Cell Physiology 290, no. 4 (April 2006): C1179—C1188. http://dx.doi.org/10.1152/ajpcell.00355.2004.
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We measured stretch-induced changes in transepithelial permeability in vitro to uncharged tracers 1.5–5.5 Å in radius to identify a critical stretch threshold associated with failure of the alveolar epithelial transport barrier. Cultured alveolar epithelial cells were subjected to a uniform cyclic (0.25 Hz) biaxial 12, 25, or 37% change in surface area (ΔSA) for 1 h. Additional cells served as unstretched controls. Only 37% ΔSA (100% total lung capacity) produced a significant increase in transepithelial tracer permeability, with the largest increases for bigger tracers. Using the permeability data, we modeled the epithelial permeability in each group as a population of small pores punctuated by occasional large pores. After 37% ΔSA, increases in paracellular transport were correlated with increases in the radii of both pore populations. Inhibition of protein kinase C and tyrosine kinase activity during stretch did not affect the permeability of stretched cells. In contrast, chelating intracellular calcium and/or stabilizing F-actin during 37% ΔSA stretch reduced but did not eliminate the stretch-induced increase in paracellular permeability. These results provide the first in vitro evidence that large magnitudes of stretch increase paracellular transport of micromolecules across the alveolar epithelium, partially mediated by intracellular signaling pathways. Our monolayer data are supported by whole lung permeability results, which also show an increase in alveolar permeability at high inflation volumes (20 ml/kg) at the same rate for both healthy and septic lungs.
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Ornelas, Alfredo, Alexander S. Dowdell, J. Scott Lee, and Sean P. Colgan. "Microbial Metabolite Regulation of Epithelial Cell-Cell Interactions and Barrier Function." Cells 11, no. 6 (March 10, 2022): 944. http://dx.doi.org/10.3390/cells11060944.
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Epithelial cells that line tissues such as the intestine serve as the primary barrier to the outside world. Epithelia provide selective permeability in the presence of a large constellation of microbes, termed the microbiota. Recent studies have revealed that the symbiotic relationship between the healthy host and the microbiota includes the regulation of cell–cell interactions at the level of epithelial tight junctions. The most recent findings have identified multiple microbial-derived metabolites that influence intracellular signaling pathways which elicit activities at the epithelial apical junction complex. Here, we review recent findings that place microbiota-derived metabolites as primary regulators of epithelial cell–cell interactions and ultimately mucosal permeability in health and disease.
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Shil, Aparna, Oluwatobi Olusanya, Zaynub Ghufoor, Benjamin Forson, Joanne Marks, and Havovi Chichger. "Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3." Nutrients 12, no. 6 (June 22, 2020): 1862. http://dx.doi.org/10.3390/nu12061862.
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The breakdown of the intestinal epithelial barrier and subsequent increase in intestinal permeability can lead to systemic inflammatory diseases and multiple-organ failure. Nutrition impacts the intestinal barrier, with dietary components such as gluten increasing permeability. Artificial sweeteners are increasingly consumed by the general public in a range of foods and drinks. The sweet taste receptor (T1R3) is activated by artificial sweeteners and has been identified in the intestine to play a role in incretin release and glucose transport; however, T1R3 has not been previously linked to intestinal permeability. Here, the intestinal epithelial cell line, Caco-2, was used to study the effect of commonly-consumed artificial sweeteners, sucralose, aspartame and saccharin, on permeability. At high concentrations, aspartame and saccharin were found to induce apoptosis and cell death in intestinal epithelial cells, while at low concentrations, sucralose and aspartame increased epithelial barrier permeability and down-regulated claudin 3 at the cell surface. T1R3 knockdown was found to attenuate these effects of artificial sweeteners. Aspartame induced reactive oxygen species (ROS) production to cause permeability and claudin 3 internalization, while sweetener-induced permeability and oxidative stress was rescued by the overexpression of claudin 3. Taken together, our findings demonstrate that the artificial sweeteners sucralose, aspartame, and saccharin exert a range of negative effects on the intestinal epithelium through the sweet taste receptor T1R3.
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Becker, Ulrich, Carsten Ehrhardt, Marc Schneider, Leon Muys, Dorothea Gross, Klaus Eschmann, Ulrich F. Schaefer, and Claus-Michael Lehr. "A Comparative Evaluation of Corneal Epithelial Cell Cultures for Assessing Ocular Permeability." Alternatives to Laboratory Animals 36, no. 1 (February 2008): 33–44. http://dx.doi.org/10.1177/026119290803600106.
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The purpose of this study was to evaluate the potential value of different epithelial cell culture systems as in vitro models for studying corneal permeability. Transformed human corneal epithelial (HCE-T) cells and Statens Serum Institut rabbit corneal (SIRC) cells were cultured on permeable filters. SkinEthic human corneal epithelium (S-HCE) and Clonetics human corneal epithelium (C-HCE) were received as ready-to-use systems. Excised rabbit corneas (ERCs) and human corneas (EHCs) were mounted in Ussing chambers, and used as references. Barrier properties were assessed by measuring transepithelial electrical resistance, and by determining the apparent permeability of markers with different physico–chemical properties, namely, fluorescein, sodium salt; propranolol hydrochloride; moxaverine hydrochloride; timolol hydrogenmaleate; and rhodamine 123. SIRC cells and the S-HCE failed to develop epithelial barrier properties, and hence were unable to distinguish between the permeation markers. Barrier function and the power to differentiate compound permeabilities were evident with HCE-T cells, and were even more pronounced in the case of C-HCE, corresponding very well with data from ERCs and EHCs. A net secretion of rhodamine 123 was not observed with any of the models, suggesting that P-glycoprotein or similar efflux systems have no significant effects on corneal permeability. Currently available corneal epithelial cell culture systems show differences in epithelial barrier function. Systems lacking functional cell–cell contacts are of limited value for assessing corneal permeability, and should be critically evaluated for other purposes.
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Peterson, M. W., M. E. Walter, and T. J. Gross. "Asbestos directly increases lung epithelial permeability." American Journal of Physiology-Lung Cellular and Molecular Physiology 265, no. 3 (September 1, 1993): L308—L317. http://dx.doi.org/10.1152/ajplung.1993.265.3.l308.
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Asbestos causes the fibrotic lung disease asbestosis, but the biologic basis for this is unknown. Lung epithelial dysfunction including increased permeability is hypothesized to contribute to lung scarring in other forms of pulmonary fibrosis. Lung epithelial permeability is increased in both animals and humans exposed to asbestos. It is not known whether the increased epithelial permeability results from direct effects of asbestos or occurs as a result of the inflammatory reaction to asbestos fibers. To address this question we used a cultured human lung epithelial model, and we measured the direct effect of asbestos on lung epithelial barrier integrity as measured by mannitol permeability. We exposed the monolayer to chryogenically ground, respirable-sized chrysotile asbestos particles. This chrysotile asbestos caused a dose- and time-dependent increase in mannitol permeability across the epithelial monolayer. Increased mannitol permeability occurred both in the presence and in the absence of serum, was not due to cytotoxicity as measured by lactate dehydrogenase release, and was not associated with altered actin cytoskeleton at the light microscopic level. Permeability to 70 kDa neutral dextran also increased after asbestos exposure; however, the absolute permeability to dextran was less than mannitol permeability. Neither latex beads nor tantalum caused any change in permeability, suggesting that our findings are not explained by nonspecific effects of particles. Increased permeability did not reverse in the continued presence of asbestos and persisted even after removing the asbestos. Finally, surface-bound iron did not appear to be necessary for this effect because neither chelating iron with deferoxamine nor iron-loading the asbestos altered the effect on mannitol permeability. These results show that asbestos has direct effects on lung epithelial permeability. Together with the recent observation that asbestos directly increases epithelial fibrinolytic activity, our results suggest a novel mechanism for asbestos-induced lung injury.
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Kelly, Scott P., and Chris M. Wood. "Effect of cortisol on the physiology of cultured pavement cell epithelia from freshwater trout gills." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, no. 3 (September 1, 2001): R811—R820. http://dx.doi.org/10.1152/ajpregu.2001.281.3.r811.
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Cortisol had dose-dependent effects on the electrophysiological, permeability, and ion-transporting properties of cultured pavement cell epithelia derived from freshwater rainbow trout gills and grown on cell culture filter supports. Under both symmetrical (L15 media apical/L15 media basolateral) and asymmetrical (freshwater apical/L15 media basolateral) culture conditions, cortisol treatment elevated transepithelial resistance, whereas permeability of epithelia to a paracellular permeability marker (polyethylene glycol-4000) decreased. Cortisol did not alter the Na+-K+-ATPase activity or the total protein content of the cultured preparations. During 24-h exposure to asymmetrical conditions, the net loss rates of both Na+ and Cl− to the water decreased with increasing cortisol dose, an important adaptation to dilute media. Unidirectional Na+ and Cl− flux measurements and the application of the Ussing flux-ratio criterion revealed cortisol-induced active uptake of both Na+ and Cl− under symmetrical culture conditions together with an increase in transepithelial potential (positive on the basolateral side). Under asymmetrical conditions, cortisol did not promote active ion transport across the epithelium. These experiments provide evidence for the direct action of cortisol on cultured pavement cell epithelia and, in particular, emphasize the importance of cortisol for limiting epithelial permeability.
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Nusrat, A., J. R. Turner, and J. L. Madara. "IV. Regulation of tight junctions by extracellular stimuli: nutrients, cytokines, and immune cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 279, no. 5 (November 1, 2000): G851—G857. http://dx.doi.org/10.1152/ajpgi.2000.279.5.g851.
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The epithelial lining of the gastrointestinal tract forms a regulated, selectively permeable barrier between luminal contents and the underlying tissue compartments. Permeability across the epithelium is, in part, determined by the rate-limiting barrier of the paracellular pathway—the most apical intercellular junction referred to as the tight junction (TJ). The TJ is composed of a multiprotein complex that affiliates with the underlying apical actomyosin ring. TJ structure and function, and therefore epithelial permeability, are influenced by diverse physiological and pathological stimuli; here we review examples of such stimuli that are detected at the cell surface. For example, luminal glucose induces an increase in paracellular permeability to small molecules. Similarly, but by other means, cytokines and leukocytes in the vicinity of the epithelium also regulate TJ structure and paracellular permeability by influencing the TJ protein complex and/or its association with the underlying actin cytoskeleton.
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Kanwar, S., J. L. Wallace, D. Befus, and P. Kubes. "Nitric oxide synthesis inhibition increases epithelial permeability via mast cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 266, no. 2 (February 1, 1994): G222—G229. http://dx.doi.org/10.1152/ajpgi.1994.266.2.g222.
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In this study, we assessed the involvement of mast cells and mast cell-derived mediators in the enhanced epithelial permeability associated with nitric oxide synthesis inhibition. Permeability of the small bowel was assessed by measuring the clearance of a small marker (51Cr-labeled EDTA) from blood to lumen in the presence of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). L-NAME caused a very rapid (10 min) increase in epithelial permeability, reaching peak values (sixfold increase) within 20 min. Two mast cell stabilizers, doxantrazole and lodoxamide, greatly attenuated the rise in mucosal permeability. Rat mast cell protease II activity (marker of mucosal mast cell degranulation) was increased significantly only in the plasma of L-NAME-treated animals. Chronic dexamethasone administration depleted rats of mucosal mast cells and also prevented the L-NAME-induced rise in mucosal permeability. The increase in epithelial permeability was mediated by a number of mediators: platelet-activating factor caused the early rise in epithelial permeability, and histamine caused the later increase in epithelial permeability. Superoxide dismutase attenuated the L-NAME-induced rise in epithelial permeability, suggesting an important and continuous role for superoxide. Transepithelial flux of 51Cr-EDTA across rat intestinal epithelial cell monolayers did not increase in the presence of L-NAME, suggesting that inhibition of nitric oxide does not directly cause epithelial permeability alterations, whereas the in vivo data implicate a potential role for the mast cell. In conclusion, nitric oxide synthesis inhibition activates mast cells in the mucosa and consequently increases epithelial permeability.
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Yamaya, M., K. Sekizawa, T. Masuda, M. Morikawa, T. Sawai, and H. Sasaki. "Oxidants affect permeability and repair of the cultured human tracheal epithelium." American Journal of Physiology-Lung Cellular and Molecular Physiology 268, no. 2 (February 1, 1995): L284—L293. http://dx.doi.org/10.1152/ajplung.1995.268.2.l284.
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To examine the effects of oxidants on the airway epithelial barrier functions, human tracheal epithelial cells were cultured on porous filter membrane. Glucose oxidase (GO; 10 U/ml), hydrogen peroxide (H2O2; 4 x 10(-3) M), and xanthine (5 x 10(-4) M) plus xanthine oxidase (20 mU/ml) (X-XO) significantly increased electrical conductance across epithelial membrane (G), short-circuit current (Isc) measured with Ussing's chamber methods, and [3H]mannitol flux through the cultured epithelium. Increases in G and Isc induced by oxidants were significantly inhibited by catalase (1,000 U/ml) and the protein kinase C inhibitor staurosporine (10(-7) M), but superoxide dismutase (SOD; 100 U/ml) was without effect. GO, H2O2, and X-XO inhibited the epithelial cell growth, [3H]thymidine incorporation by the cells, and epithelial repair of artificially produced focal epithelial defects (1–2 mm diam) on plastic vessels. Catalase also inhibited effects induced by oxidants on cell growth and proliferation. These results suggest that oxidants reduce tracheal epithelial barrier functions by damaging tight junctions and inhibiting cell proliferation, and these effects of oxidants on epithelial cells may be mediated by H2O2 rather than superoxide anion and by activation of protein kinase C.
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Mullin, James M., James M. Leatherman, Mary Carmen Valenzano, Erika Rendon Huerta, Jon Verrechio, David M. Smith, Karen Snetselaar, Mantao Liu, Mary Kay Francis, and Christian Sell. "Ras Mutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes." Molecular Biology of the Cell 16, no. 12 (December 2005): 5538–50. http://dx.doi.org/10.1091/mbc.e05-04-0294.
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Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of d-mannitol increases sixfold but transepithelial electrical resistance increases >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to d-mannitol (Mr 182), polyethylene glycol (Mr 4000), and 10,000-Mr methylated dextran but not to 2,000,000-Mr methylated dextran. This implies a “ceiling” on the size of solutes that can cross a ras-mutated epithelial barrier and therefore that the increased permeability is not due to loss of cells or junctions. Although the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins-3 and -5 remained unchanged. An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier.
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Milks, L. C., G. P. Conyers, and E. B. Cramer. "The effect of neutrophil migration on epithelial permeability." Journal of Cell Biology 103, no. 6 (December 1, 1986): 2729–38. http://dx.doi.org/10.1083/jcb.103.6.2729.
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To reach an inflammatory lesion, neutrophils must frequently traverse the epithelium of an infected organ. Whether the actual migration of neutrophils alters the epithelial permeability is unknown. Through the use of an in vitro model system it was possible to directly determine the effect of neutrophil emigration on the transepithelial electrical resistance of the monolayer. Human neutrophils (5 X 10(6) cells/ml) were placed in the upper compartment of a combined chemotaxis/resistance chamber and stimulated for 40 min by a gradient of 10(-7) M n-formyl-methionyl-leucyl-phenylalanine to traverse a confluent monolayer of canine kidney epithelial cells grown on micropore filters. Neither the chemoattractant alone (10(-5)-10(-9) M) nor the accumulation of an average of eight neutrophils per millimeter of epithelium lowered the transepithelial electrical resistance. However, under certain conditions the migration of neutrophils temporarily increased the permeability of the monolayer. The resistance fell approximately 48% within 5 min if the migratory cells were stimulated to reverse their migration across the same monolayer. As re-migration continued, the resistance returned to its initial levels within 60 min. Doubling the initial neutrophil concentration to 10 X 10(6) cells/ml resulted in the accumulation of an average of 66 neutrophils per millimeter of epithelium and an average fall in resistance of 46% (r = 0.98; P less than 0.001) in 40 min. If the resistance had fallen less than 45%, removal of the neutrophils remaining in the upper compartment resulted in a return of the transepithelial electrical resistance to its initial level within 65 min. However, when the fall was greater than 45%, the resistance only recovered to 23.5% of its initial levels within the same time frame. Thus, these results suggest that the integrity of an epithelium can, under certain conditions, be affected by the emigration of neutrophils, but that this effect is either completely or partially reversible within 65 min.
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Mariadason, J. M., A. Catto-Smith, and P. R. Gibson. "Modulation of distal colonic epithelial barrier function by dietary fibre in normal rats." Gut 44, no. 3 (March 1, 1999): 394–99. http://dx.doi.org/10.1136/gut.44.3.394.
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BACKGROUNDDietary fibre influences the turnover and differentiation of the colonic epithelium, but its effects on barrier function are unknown.AIMSTo determine whether altering the type and amount of fibre in the diet affects paracellular permeability of intestinal epithelium, and to identify the mechanisms of action.METHODSRats were fed isoenergetic low fibre diets with or without supplements of wheat bran (10%) or methylcellulose (10%), for four weeks. Paracellular permeability was determined by measurement of conductance and 51Cr-EDTA flux across tissue mounted in Ussing chambers. Faecal short chain fatty acid (SCFA) concentrations were assessed by gas chromatography, epithelial kinetics stathmokinetically, and mucosal brush border hydrolase activities spectrophotometrically.RESULTSBody weight was similar across the dietary groups. Conductance and 51Cr-EDTA flux were approximately 25% higher in animals fed no fibre, compared with those fed wheat bran or methylcellulose in the distal colon, but not in the caecum or jejunum. Histologically, there was no evidence of epithelial injury or erosion associated with any diet. The fibres exerted different spectra of effects on luminal SCFA concentrations and pH, and on mucosal indexes, but both bulked the faeces, were trophic to the epithelium, and stimulated expression of a marker of epithelial differentiation.CONCLUSIONSBoth a fermentable and a non-fermentable fibre reduce paracellular permeability specifically in the distal colon, possibly by promoting epithelial cell differentiation. The mechanisms by which the two fibres exert their effects are likely to be different.
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Grundstrom, N., E. G. Lindstrom, K. L. Axelsson, and R. G. Andersson. "Epithelial modulation of allergen and drug effects in guinea pig airways." Journal of Applied Physiology 72, no. 5 (May 1, 1992): 1953–59. http://dx.doi.org/10.1152/jappl.1992.72.5.1953.
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The effect of egg albumin (EA) challenge on tracheal tube preparations from sensitized guinea pigs was studied with regard to EA permeability, histamine release and penetrability, and the contractile response of the preparation. We used a plethysmographic method that allowed simultaneous measurement of changes in smooth muscle tension and collection of samples for determination of mediators. Our results clearly show that epithelial damage potentiates the contractile response to histamine, potassium ions, and acetylcholine. Epithelial damage did not alter the maximal contractile response in preparations challenged with high antigen concentrations (EA, 1 mg/ml), but histamine release measured in the perfusate increased substantially. The permeability of the preparations to EA was greater when the epithelium was damaged. No increase in the permeability in response to the EA challenge was observed. The present study has demonstrated that guinea pig airway epithelium constitutes a barrier for both antigen and drugs. We also present a method for recording contractile responses from intact whole tracheal preparations, in which the epithelium can still act as a barrier, as is the case in vivo.
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Su, Xiaomin, Jianmei Wei, Houbao Qi, Mengli Jin, Qianjing Zhang, Yuan Zhang, Chunze Zhang, and Rongcun Yang. "LRRC19 Promotes Permeability of the Gut Epithelial Barrier Through Degrading PKC-ζ and PKCι/λ to Reduce Expression of ZO1, ZO3, and Occludin." Inflammatory Bowel Diseases 27, no. 8 (January 27, 2021): 1302–15. http://dx.doi.org/10.1093/ibd/izaa354.
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Abstract Background A dysfunctional gut epithelial barrier allows the augmented permeation of endotoxins, luminal antigens, and bacteria into the bloodstream, causing disease. The maintenance of gut epithelial barrier integrity may be regulated by multiple factors. Herein we analyze the role of leucine-rich repeat-containing protein 19 (LRRC19) in regulating the permeability of the gut epithelial barrier. Methods We utilized Lrrc19 knockout (KO) mice and clinical samples through transmission electron, intestinal permeability assay, Western blot, and immunofluorescence staining to characterize the role of LRRC19 in the permeability of the gut epithelial barrier. Results We found that LRRC19, which is expressed in gut epithelial cells, impairs gut barrier function. Transmission electron micrographs revealed a tighter junction and narrower gaps in the colon epithelium cells in LRRC19 KO mice. There were lower levels of serum lipopolysaccharide and 4 kDa-fluorescein isothiocyanate-dextran after gavage in LRRC19 KO mice than in wild-type mice. We found that LRRC19 could reduce the expression of zonula occludens (ZO)-1, ZO-3, and occludin in the colonic epithelial cells. The decreased expression of ZO-1, ZO-3, and occludin was dependent on degrading protein kinase C (PKC) ζ and PKCι/λ through K48 ubiquitination by LRRC19. The expression of LRRC19 was also negatively correlated with ZO-1, ZO-3, occludin, PKCζ, and PKCι/λ in human colorectal cancers. Conclusions The protein LRRC19 can promote the permeability of the gut epithelial barrier through degrading PKC ζ and PKCι/λ to reduce the expression of ZO-1, ZO-3, and occludin.
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Guo, Y., L. A. Schneider, and O. D. Wangensteen. "HOCl effects on tracheal epithelium: conductance and permeability measurements." Journal of Applied Physiology 78, no. 4 (April 1, 1995): 1330–38. http://dx.doi.org/10.1152/jappl.1995.78.4.1330.
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It is speculated that hypochlorous acid (HOCl), produced by neutrophils, can disrupt the tracheal epithelial barrier without damage to epithelial cells. This was investigated with solute permeability (P) and electrical conductance (G) measurements on tracheae from 4-wk-old rabbits. A new system for epithelial bioelectric measurements on intact tracheae was developed and validated. Control values of G, short-circuit current, and spontaneous potential difference were 4.9 +/- 0.5 (SE) mS/cm2, 42.6 +/- 4.7 microA/cm2, and 8.9 +/- 1.0 mV (lumen negative), respectively (n = 5). Control P values for sucrose, inulin, and Dextran-20 were 5.14 +/- 0.48, 0.63 +/- 0.10, and 0.057 +/- 0.007 x 10(-7) cm/s, respectively (n = 6). Tracheae treated with HOCl had no effect; 6 mM HOCl, a concentration that could exist in infected airways, significantly increased both P and G (about two- to fourfold) without damage to epithelial cells; and 12 and 30 mM HOCl caused more than 10-fold increases for both P and G with cell disruption. Vitamin C blocked epithelial damage caused by 30 mM HOCl. Tracheae from 1-wk-old rabbits were significantly more sensitive to HOCl than those from 4-wk-old or adult rabbits. This study validated a new bioelectric measurement system and showed that HOCl has both dose- and age-dependent effects on the tracheal epithelium.
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Kudoh, Ichidai, Mika Ohtake, Hideo Nishizawa, Kiyoyasu Kurahashi, Satoshi Hattori, Fukuichiro Okumura, Jean-Francois Pittet, and Jeanine Wiener-Kronish. "The Effect of Pentoxifylline on Acid-induced Alveolar Epithelial Injury." Anesthesiology 82, no. 2 (February 1, 1995): 531–41. http://dx.doi.org/10.1097/00000542-199502000-00023.
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Background Acid instillation into one lung is known to cause an increase in the permeability of the endothelium to protein in both the instilled and the contralateral lungs. Activated neutrophils are believed to be involved in causing this increased permeability. Pentoxifylline, a drug used in clinical practice, has multiple effects on neutrophils, including inhibition of phagocytosis, degranulation, and superoxide generation. This study investigated whether pretreatment with pentoxifylline would protect the alveolar epithelium or lung endothelium from injury. Methods The effect of acid instillation into one lung of anesthetized rabbits using several quantitative parameters was investigated. The quantification of the bidirectional movement of the alveolar (125I-albumin) and the circulating protein tracers (131I-albumin) was used as a measurement of the permeabilities of the lung epithelium and the lung endothelium in the acid-instilled lung. Bronchoalveolar lavage and measurement of the entry of the circulating protein tracer were used to assess the permeabilities of these barriers in the noninstilled lung. Results The instillation of HCl (pH 1.25, 1.2 ml/kg) into the right lung resulted in an increase in the protein permeability of the right lung's alveolar epithelium and endothelium as well as an increase in the permeability to protein of the left lung's endothelium. Pentoxifylline pretreatment attenuated the increase in the endothelial permeability of both lungs by 50% and restored the PaO2/FIO2 to normal in the pretreated animals exposed to acid injury. Conclusions Acid aspiration causes a dramatic increase in the alveolar epithelial permeability of the acid-instilled lung, but the permeability of the alveolar epithelium of the contralateral lung remains normal. In contrast, unilateral acid instillation causes an increase in the permeability of the endothelium of both lungs. The increase in endothelial permeability can be attenuated by pretreatment with pentoxifylline administration, and this leads to restoration of normal gas exchange.
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Lin, Yuli, Bingji Li, Xuguang Yang, Ting Liu, Tiancong Shi, Bo Deng, Yubin Zhang, Lijun Jia, Zhengfan Jiang, and Rui He. "Non-hematopoietic STAT6 induces epithelial tight junction dysfunction and promotes intestinal inflammation and tumorigenesis." Mucosal Immunology 12, no. 6 (September 18, 2019): 1304–15. http://dx.doi.org/10.1038/s41385-019-0204-y.
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Abstract Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancing-effect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSS-induced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.
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Verghese, George M., Michael F. Gutknecht, and George H. Caughey. "Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor." American Journal of Physiology-Cell Physiology 291, no. 6 (December 2006): C1258—C1270. http://dx.doi.org/10.1152/ajpcell.00637.2005.
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Prostasin, a trypsinlike serine peptidase, is highly expressed in prostate, kidney, and lung epithelia, where it is bound to the cell surface, secreted, or both. Prostasin activates the epithelial sodium channel (ENaC) and suppresses invasion of prostate and breast cancer cells. The studies reported here establish mechanisms of membrane anchoring and secretion in kidney and lung epithelial cells and demonstrate a critical role for prostasin in regulating epithelial monolayer function. We report that endogenous mouse prostasin is glycosylphosphatidylinositol (GPI) anchored to the cell surface and is constitutively secreted from the apical surface of kidney cortical collecting duct cells. Using site-directed mutagenesis, detergent phase separation, and RNA interference approaches, we show that prostasin secretion depends on GPI anchor cleavage by endogenous GPI-specific phospholipase D1 (Gpld1). Secretion of prostasin by kidney and lung epithelial cells, in contrast to prostate epithelium, does not depend on COOH-terminal processing at conserved Arg322. Using stably transfected M-1 cells expressing wild-type, catalytically inactive, or chimeric transmembrane (not GPI)-anchored prostasins we establish that prostasin regulates transepithelial resistance, current, and paracellular permeability by GPI anchor- and protease activity-dependent mechanisms. These studies demonstrate a novel role for prostasin in regulating epithelial monolayer resistance and permeability in kidney epithelial cells and, furthermore, show specifically that prostasin is a critical regulator of transepithelial ion transport in M-1 cells. These functions depend on the GPI anchor as well as the peptidase activity of prostasin. These studies suggest that cell-specific Gpld1- or peptidase-dependent pathways for prostasin secretion may control prostasin functions in a tissue-specific manner.
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Gookin, Jody L., Joseph A. Galanko, Anthony T. Blikslager, and Robert A. Argenzio. "PG-mediated closure of paracellular pathway and not restitution is the primary determinant of barrier recovery in acutely injured porcine ileum." American Journal of Physiology-Gastrointestinal and Liver Physiology 285, no. 5 (November 2003): G967—G979. http://dx.doi.org/10.1152/ajpgi.00532.2002.
Full textAbstract:
Small bowel epithelium is at the frontline of intestinal barrier function. Restitution is considered to be the major determinant of epithelial repair, because function recovers in parallel with restitution after acute injury. As such, studies of intact mucosa have largely been replaced by migration assays of cultured epithelia. These latter studies fail to account for the simultaneous roles played by villous contraction and paracellular permeability in recovery of barrier function. NSAIDs result in increased intestinal permeability and disease exacerbation in patients with inflammatory bowel disease (IBD). Thus we examined the reparative attributes of endogenous PGs after injury of ileal mucosa by deoxycholate (6 mM) in Ussing chambers. Recovery of transepithelial electrical resistance (TER) from 20-40 Ω·cm2 was abolished by indomethacin (Indo), whereas restitution of 40-100% of the villous surface was unaffected despite concurrent arrest of villous contraction. In the presence of PG, resident crypt and migrating epithelial cells were tightly apposed. In tissues treated with Indo, crypt epithelial cells had dilated intercellular spaces that were accentuated in the migrating epithelium. TER was fully rescued from the effects of Indo by osmotic-driven collapse of the paracellular space, and PG-mediated recovery was significantly impaired by blockade of Cl- secretion. These studies are the first to clearly distinguish the relative contribution of paracellular resistance vs. restitution to acute recovery of epithelial barrier function. Restitution was ineffective in the absence of PG-mediated paracellular space closure. Failure of PG-mediated repair mechanisms may underlie barrier failure resulting from NSAID use in patients with underlying enteropathy.
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Ayala-Torres, Carlos, Susanne M. Krug, Jörg D. Schulzke, Rita Rosenthal, and Michael Fromm. "Tricellulin Effect on Paracellular Water Transport." International Journal of Molecular Sciences 20, no. 22 (November 14, 2019): 5700. http://dx.doi.org/10.3390/ijms20225700.
Full textAbstract:
In epithelia, large amounts of water pass by transcellular and paracellular pathways, driven by the osmotic gradient built up by the movement of solutes. The transcellular pathway has been molecularly characterized by the discovery of aquaporin membrane channels. Unlike this, the existence of a paracellular pathway for water through the tight junctions (TJ) was discussed controversially for many years until two molecular components of paracellular water transport, claudin-2 and claudin-15, were identified. A main protein of the tricellular TJ (tTJ), tricellulin, was shown to be downregulated in ulcerative colitis leading to increased permeability to macromolecules. Whether or not tricellulin also regulates water transport is unknown yet. To this end, an epithelial cell line featuring properties of a tight epithelium, Madin-Darby canine kidney cells clone 7 (MDCK C7), was stably transfected with small hairpin RNA (shRNA) targeting tricellulin, a protein of the tTJ essential for the barrier against passage of solutes up to 10 kDa. Water flux was induced by osmotic gradients using mannitol or 4 and 40 kDa-dextran. Water flux in tricellulin knockdown (KD) cells was higher compared to that of vector controls, indicating a direct role of tricellulin in regulating water permeability in a tight epithelial cell line. We conclude that tricellulin increases water permeability at reduced expression.
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McCarey, Bernard E., and T. Al Reaves. "Noninvasive measurement of corneal epithelial permeability." Current Eye Research 14, no. 6 (January 1995): 505–10. http://dx.doi.org/10.3109/02713689509003762.
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O'Doherty, M. J., C. J. Page, C. Harrington, T. Nunan, and G. Savidge. "Haemophilia, AIDS and lung epithelial permeability." European Journal of Haematology 44, no. 4 (April 24, 2009): 252–56. http://dx.doi.org/10.1111/j.1600-0609.1990.tb00388.x.
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Nelson, JD. "Tear turnover and corneal epithelial permeability." American Journal of Ophthalmology 121, no. 1 (January 1996): 116. http://dx.doi.org/10.1016/s0002-9394(14)70573-2.
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