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PubMed1982

On tight-junction structure.

We have analyzed previous thin-section and freeze-fracture observations of the tight junction. We propose that the tight-junction strands represent intramembranous, cylindrical, inverted micelles. At the junctional site, the exoplasmic halves of the plasma membranes are fused into a continuous leaflet. Therefore, topologically and structurally the tight junction is viewed as the outcome of a process of linear fusion between the plasma membranes of epithelial cells. The extracellular spaces delimited by the junction are separated by two distinct exoplasmic membrane halves and the cylindrical micelles. Junctional stability, fostered by the environmental symmetry of the cytoplasmic milieux of contiguous cells, may be maintained by transmembrane integral proteins at the junctional site, interacting at the cytoplasmic surface with cytoskeletal components.

Animals↗
PubMed1993

Tight junctional structure and permeability of porcine jejunum after enterotoxic Escherichia coli infection.

Tight junctional structure and macromolecular permeability were tested in four three-week-old piglets, experimentally infected with the enterotoxigenic Escherichia coli (ETEC) strain O149 K91 K88. Histologically, only minor microscopic evidence of inflammation and little or no architectural changes in the jejunal mucosa were observed. A significant decrease in tight junctional strand numbers occurred, without a concomitant decrease in tight junctional depth. The permeability of the porcine jejunal epithelium to horseradish peroxidase did not change after the ETEC infection.

Animals↗
PubMed2002

Nonreceptor tyrosine kinase c-Yes interacts with occludin during tight junction formation in canine kidney epithelial cells.

Occludin is an integral membrane protein that is tyrosine phosphorylated when localized at tight junctions. When Ca(2+) was depleted from the culture medium, occludin tyrosine phosphorylation was diminished from Madin-Darby canine kidney epithelial cells in 2 min. This dephosphorylation was correlated with a significant reduction in transepithelial electrical resistance (TER), indicating a global loss of the tight junction barrier function. Reconstitution of Ca(2+) resulted in a robust tyrosine rephosphorylation of occludin that was temporally associated with an increase in TER. Moreover, we demonstrate in this study that occludin was colocalized with the nonreceptor tyrosine kinase c-Yes at cell junction areas and formed an immunoprecipitable complex with c-Yes in vivo. This complex dissociated when the cells were incubated in medium without Ca(2+) or treated with a c-Yes inhibitor, CGP77675. In the presence of CGP77675 after Ca(2+) repletion, occludin tyrosine phosphorylation was completely abolished and both tight junction formation and the increase of the TER were inhibited. Our study thus provides strong evidence that occludin tyrosine phosphorylation is tightly linked to tight junction formation in epithelial cells, and that the nonreceptor tyrosine kinase c-Yes is involved in the regulation of this process.

Animals↗
PubMed1994

Osmotic water flow pathways across Necturus gallbladder: role of the tight junction.

To explore the quantitative significance of passive water flow through tight junctions of leaky epithelia, transepithelial water flow rates were measured in Necturus gallbladder mounted in chambers. Osmotic flows generated by raffinose gradients were asymmetrical with the greater flow in the mucosal-to-serosal direction. In tissue fixed in situ, intercellular spaces were dilated during mucosal-to-serosal flow and closed during serosal-to-mucosal flow. Tight junctions were focally separated (blistered), which correlated with the magnitude of mucosal-to-serosal flow. Blisters were not observed during serosal-to-mucosal flow or in nontransporting gallbladders. In freeze-fracture replicas, blisters appeared as pockets between intramembranous strands. Protamine, which decreases electrical conductance and increases depth and complexity of the tight junction, reduced osmotic water flow by approximately 30% in the mucosal-to-serosal direction (100 mosmol/kg gradient) without altering serosal-to-mucosal flow. We suggest that in the steady state, at least 30% of osmotically driven water passes transjunctionally in the mucosal-to-serosal direction, but flow is transcellular in the serosal-to-mucosal direction. Directionally divergent pathways may account for flow asymmetry.

Animals↗
PubMed1997

Differential distribution of the tight-junction-associated protein ZO-1 isoforms alpha+ and alpha- in guinea pig Sertoli cells: a possible association with F-actin and G-actin.

To elucidate the significance of alpha- and alpha+ isoforms of the tight-junction-associated protein ZO-1 in Sertoli cell tight junction regulation, taking into consideration that different isoforms are expressed in cells with different junctional morphologies, we investigated whether alpha- and alpha+ are differentially associated with junctions forming the continuous occluding zonules responsible for the blood-testis barrier, and/or with junctions forming the focal discontinuous occluding zonules. In addition, since Sertoli cells contact Sertoli cells and germ cells, we investigated whether each isoform is differentially associated with distinct classes of germ cells. Our immunoblot analyses of isolated seminiferous tubules, using affinity-purified polyclonal antibodies recognizing rat and human alpha- and alpha+, showed that guinea pig testis contained the two ZO-1 isoforms initially described in rat and human kidneys, and that alpha+ and alpha- were predominantly expressed during puberty and adulthood, respectively, indicating that alpha+ was predominant during periods of increased junction assembly/disassembly. We used the same antibodies and immunoperoxidase labeling on fetal, neonatal, pubertal, and adult guinea pig testes sections. Both isoforms were expressed at the site of Sertoli cell-Sertoli cell and Sertoli cell-germ cell junctions in the seminiferous epithelium, before and after birth, and both were localized in continuous and in discontinuous tight junctions. However, the distribution of alpha- and alpha+ was not the same in different locations of the tight junctions. Only alpha- was incorporated into junctions joining the Sertoli cells to all classes of germ cells. The alpha+ involved junctions joining Sertoli cells to particular classes of germ cells, suggesting that Sertoli cell expression of ZO-1 isoforms could be regulated by unique germ cell-Sertoli cell contacts. Conversely, we found a correspondence between the distribution of F-actin and ZO-1alpha+, indicating that the spatial organization of the subsurface actin accompanying cell junctions may affect alpha+/alpha(-)-plasma membrane association.

Actins↗
PubMed1977

Effect of protonated 2,4,6-triaminopyrimidine, a tight junction blocker, on intestinal transport in dog ileum in vivo.

Previous in vitro experiments suggest that protonated 2,4,6-triaminopyrimidine (TAP+) inhibits passive Na+ movement across tight junctions of various epithelial tissues. So far no evidence has been found that TAP+ interferes with other mucosal transport processes. Because blockage of the tight junctions would be a promising tool in studying intestinal transport physiology, the effect of TAP+ was investigated in the dog ileum in vivo. When TAP+ was added to a sodium-free mannitol solution, the transepithelial sodium diffusion potential was significantly decreased (60% inhibition with 34 mm TAP+); this would be expected if TAP+ inhibited NA+ permeation through tight junctions. However, TAP+ was also found to diminish Na+ and Cl- absorption. Furthermore, TAP+ increased unidirectional Na+ flux from plasma to lumen; this is opposite to the expected result of tight junction blockage. In addition, TAP+ reduced glucose, fructose, and xylose absorption by about 50%. In ileal loops exposed to cholera toxin, TAP+ enhanced secretion by a rate equal to the rate by which it reduced absorption in loops not exposed to cholera toxin. All changes induced by TAP+ approached normal within 4 hr of its removal from the perfusate. TAP+ did not cause nay mucosal damage that could be detected by protein leakage or by light microscopy. These studies show that TAP+ has many effects on intestinal transport processes that cannot be explained on the basis of tight junction blockage.

Animals↗
PubMed1983

Participation of plasma membrane proteins in the formation of tight junctions by cultured epithelial cells.

Measurements of the transepithelial electrical resistance correlated with freeze-fracture observations have been used to study the process of tight junction formation under various experimental conditions in monolayers of the canine kidney epithelial cell line MDCK. Cells derived from previously confluent cultures and plated immediately after trypsin- EDTA dissociation develop a resistance that reaches its maximum value of several hundred ohms-cm(2) after approximately 24 h and falls to a steady-state value of 80-150 ohms- cm(2) by 48 h. The rise in resistance and the development of tight junctions can be completely and reversibly prevented by the addition of 10 mug/ml cycloheximide at the time of plating, but not when this inhibitor is added more than 10 h after planting. Thus tight junction formation consists of separable synthetic and assembly phases. These two phases can also be dissociated and the requirement for protein synthesis after plating eliminated if, following trypsinization, the cells are maintained in spinner culture for 24 h before plating. The requirement for protein synthesis is restored, however, if cells maintained in spinner culture are treated with trypsin before plating. Actinomycin D prevents development of resistance only in monolayers formed from cells derived from sparse rather than confluent cultures, but new mRNA synthesis is not required if cells obtained from sparse cultures are maintained for 24 h in spinner culture before plating. Once a steady-state resistance has been reached, its maintenance does not require either mRNA or protein synthesis; in fact, inhibition of protein synthesis causes a rise in the resistance over a 30-h period. Following treatments that disrupt the junctions in steady- state monolayers recovery of resistance also does not require protein synthesis. These observations suggest that proteins are involved in tight junction formation. Such proteins, which do not turn over rapidly under steady-state conditions, are destroyed by trypsinization and can be resynthesized in the absence of stable cell-cell or cell-substratum contact. Messenger RNA coding for proteins involved in tight junction formation is stable except when cells are sparsely plated, and can also be synthesized without intercellular contacts or cell-substratum attachment.

Animals↗
PubMed2001

Tight junctional changes upon microwave and x-ray irradiation.

Tight junctions (zonulae occludentes, ZO) are cellularly regulated dynamic structures sensitive to environmental stress agents including ionizing radiation. Radiation induced pathological alterations of the small intestine (gastrointestinal radiation syndrome) are related to altered ZO-mediated paracellular transport. We carried out a quantitative morphological evaluation of the murine jejunal epithelial tight junctional structure in freeze fracture replicas as changed upon whole body X-ray irradiation and low energy microwave exposition. X-ray treatment (4 Gy, 1, 24 h) brought about a partial dearrangement of the ZO strand network which regenerated only partially by 24 h. This observation is in line with data on paracellular permeability increases and ZO-bound calcium drop caused by X-ray irradiation. On the other hand, microwave treatment (16 Hz-modulated 2.45 GHz wave, 1 mW/cm2 power density, I h exposition, samples at I and 3 h after exposition) did not cause dearrangement but, rather an increase in the integration of thight junctional structure, which is in agreement with an increase in cytochemically detectable ZO-bound calcium.

Animals↗
PubMed1979

Tight junctions adjacent to tumor stromal interface in human invasive transitional cell carcinomas.

Tight junctions adjacent to the tumor stromal interface in invading neoplastic cells of human urinary bladder carcinomas were observed. Basal lamina, collagen and elastic fibers, and cellular debris were found next to the tight junctions. An association between microenvironment (i.e., tumor necrosis) of the invading neoplastic cells and tight junction locations was suggested.

Carcinoma, Transitional Cell↗
PubMed1991

The role of phosphorylation in development of tight junctions in cultured renal epithelial (MDCK) cells.

We have explored the effect of the protein kinase inhibitor H7 on tight junction formation in a MDCK cell model for the development of cell-cell contact, tight junctions and epithelial polarity: the "Ca++ switch" model. In this developmental model, which is thought to mimic processes during the early morphogenesis of epithelial tissues, the protein kinase inhibitor H7 markedly inhibits the development of transepithelial resistance of confluent MDCK cells during the "switch" from low (1-5 microM) to normal (1.8 mM) Ca++ media compared with control MDCK cells. Moreover, indirect immunofluorescence using specific antisera against two tight junctional proteins, ZO1 and cingulin, revealed that H7 inhibits the sorting of these proteins from an intracellular site to the lateral surfaces of MDCK cells when the Ca++ in the medium is raised. These data suggest protein kinase mediation in sorting events that lead to the assembly of tight junctions.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1981

Effects of ovarian hormones on cell membranes in the rat uterus. II. Freeze-fracture studies on tight junctions of the lateral plasma membrane of the luminal epithelium.

Freeze-fracture techniques have been used to study tight junctions on the lateral plasma membrane of cells of the luminal epithelium of the rat uterus under various hormonal regimes. Tight junctions from ovariectomized control rats extended some 0.5 micron down the lateral membrane and the junctional strands often formed a network of closely packed, circular compartments. Following treatment of rats with estrogen for 3 days the tight junctional region still extended 0.5 micron down the lateral membrane, but the strands ran more parallel to the apical surface. They did not enclose circular compartments. After treatment with progesterone, either alone or with estrogen in such a way as to condition the ovariectomized uterus for implantation, a third pattern of junctional organization emerged. In these animals the junctional region extended 1.1 micron down the lateral membrane and the strands frequently crosslinked, enclosing compartments of varying and irregular size and shape. Our observations suggest that ovarian hormones could regulate the contents of the uterine lumen by altering the structure and extent of the tight junctions which connect the epithelial cells enclosing the lumen.

Animals↗
PubMed1994

A model for flow through discontinuities in the tight junction of the endothelial intercellular cleft.

A mathematical model for steady flow through a discontinuity in the tight junction of an endothelial intercellular cleft is presented. Subject to plausible assumptions the problem of calculating the flow in the cleft, in either the presence or the absence of a fibre matrix, reduces to the solution of Laplace's equation in a two-dimensional domain. For an idealized geometry representing a discontinuity between two semi-infinite tight junction regions, a general analytic solution is found by means of conformal mappings. The model geometry, unlike those assumed in previous studies, allows the tight junction regions to be out of alignment with each other, and even to overlap, modelling flow through a tortuous, rather than a direct, pathway. Useful asymptotic approximations for the flow rate are derived when the discontinuity is either very small or very large. For small discontinuities, the predicted flow rate is much greater than a naïve estimate based on uniform parallel flow through the discontinuity. For the special case where the tight junction regions are aligned with each other, comparison of our results with those of an approximate treatment due to Tsay et al. [Chem. Engng Commun. 82, 67-102 (1989)] shows generally very close agreement.

Animals↗
PubMed1998

Water does not flow across the tight junctions of MDCK cell epithelium.

Although it has been known for decades that the tight junctions of fluid-transporting epithelia are leaky to ions, it has not been possible to determine directly whether significant transjunctional water movement also occurs. An optical microscopic technique was developed for the direct visualization of the flow velocity profiles within the lateral intercellular spaces of a fluid-absorptive, cultured renal epithelium (MDCK) and used to determine the velocity of the fluid flow across the tight junction. The flow velocity within the lateral intercellular spaces fell to near zero adjacent to the tight junction, showing that significant transjunctional flow did not occur, even when transepithelial fluid movement was augmented by imposition of osmotic gradients.

Animals↗
PubMed1995

Glucocorticoid-induced functional polarity of growth factor responsiveness regulates tight junction dynamics in transformed mammary epithelial tumor cells.

The synthetic glucocorticoid, dexamethasone, induces the "normal-like" differentiated property of tight junction formation and suppresses growth of the Con8 mammary epithelial tumor cell line, derived from a 7,12-dimethylbenz(alpha)anthracene-induced rat mammary adenocarcinoma. Characterization of the transepithelial electrical resistance of Con8 mammary tumor cells cultured on permeable supports revealed that a novel response to dexamethasone is the generation of a polarized cell monolayer with respect to epidermal growth factor receptor responsiveness. Administration of transforming growth factor-alpha (TGF-alpha) to the basolateral, but not the apical, plasma membrane compartment disrupted the glucocorticoid-stimulated tight junction barrier. Confocal immunofluorescence microscopy revealed that dexamethasone caused the ZO-1 tight junction-associated protein to localize exclusively to the apical border of laterally adjacent membranes of the cell periphery, whereas basolateral administration of TGF-alpha caused the redistribution of ZO-1 back to disorganized aggregates along the cell periphery. In contrast, TGF-alpha was able to exert its mitogenic effects equally on both sides of the cell monolayer independent of its polarized disruption of tight junction formation. Our results represent the first evidence for a functional polarization of the epidermal growth factor receptor and strongly implicate the glucocorticoid-regulated formation of tight junctions in policing the polarized responsiveness of mammary cells to growth factors.

Adenocarcinoma↗
PubMed1985

Ca2+ depletion-induced disconnection of tight junctions in isolated rat brain microvessels.

Cerebral microvessels were isolated from rat brains. One part of the microvessel pellets was incubated for 25 or 90 min in Krebs-Henseleit bicarbonate buffer (KHB) at pH 7.5 (control group). The other part of the pellets was treated for the same periods of time with Ca2+-free KHB, containing 2.2 mM EGTA and 2 mM glucose (experimental group). Morphological changes of endothelial tight junctions were evaluated in 100 randomly selected interendothelial clefts from isolated cerebral microvessels of each groups by electron microscopy. Following 25 min of incubation time, either with Ca2+-containing or with Ca2+-free KHB, no significant changes of tight junctions were observed. After 90 min of incubation in Ca2+-free medium, 58% of tight junctions were altered (in 42% partial, and in 16% complete disconnection of tight junctions were found). This contrasted the control group, where only 14% of tight junctions were disconnected (12% partially and 2% completely). Our results are consistent with a role for intercellular Ca2+ in maintaining structural integrity of cerebral tight junctions.

Animals↗
PubMed2002

Biological responses of tight junction to ionizing radiation and electromagnetic field expostion.

The tight junctions form and regulate the paracellular barrier in the intercellular spaces between epithelial and endothelial cells. They play important roles in the cellular and pathological processes, which follow exposure to radiation. Therefore, analysis of their changes upon different kind of irradiation may help to understand the basic events governing their function and give important information for the radiobiological research and clinical practice as well. The immunohistochemical data on the distribution of occludin presented here demonstrate the breakdown of tight junctions in Madin Darby kidney cells exposed to ionizing irradiation and show, on the other hand that magnetic field exposures upon 100 microT leave the occludin staining pattern intact.

Animals↗
PubMed2000

Structural alterations of tight junctions are associated with loss of polarity in stroke-prone spontaneously hypertensive rat blood-brain barrier endothelial cells.

The mechanisms leading to stroke in stroke-prone spontaneously hypertensive rats (SHRSP) are not well understood. We tested the hypothesis that the endothelial tight junctions of the blood-brain barrier are altered in SHRSP prior to stroke. We investigated tight junctions in 13-week-old SHRSP, spontaneously hypertensive stroke-resistant rats (SHR) and age-matched Wistar-Kyoto rats (WKY) by electron microscopy and immunocytochemistry. Ultrathin sections showed no difference in junction structure of cerebral capillaries from SHRSP, SHR and WKY, respectively. However, using freeze-fracturing, we observed that the blood-brain barrier specific distribution of tight junction particles between P- and E-face in WKY (58.7+/-3.6%, P-face; 41.2+/-5.59%, E-face) and SHR (53.2+/-19. 3%, P-face; 55.6+/-13.25%, E-face) was changed to an 89.4+/-9.9% predominant E-face association in cerebral capillaries from SHRSP. However, the expression of the tight junction molecules ZO-1, occludin, claudin-1 and claudin-5 was not changed in capillaries of SHRSP. Permeability of brain capillaries from SHRSP was not different compared to SHR and WKY using lanthanum nitrate as a tracer. In contrast, analysis of endothelial cell polarity by distribution of the glucose-1 transporter (Glut-1) revealed that its abluminal:luminal ratio was reduced from 4:1 in SHR and WKY to 1:1 in endothelial cells of cerebral capillaries of SHRSP. In summary, we demonstrate that early changes exist in cerebral capillaries from a genetic model of hypertension-associated stroke. We suggest that a disturbed fence function of the tight junctions in SHRSP blood-brain barrier endothelial cells may lead to subtle changes in polarity. These changes may contribute to the pathogenesis of stroke.

Animals↗
PubMed1992

Regenerative stimulus increases hepatocyte tight junctional permeability.

Experience with young animals, animals administered certain hepatotoxins and animals with two-thirds hepatectomy suggests that tight junctional permeability is increased in states characterized by architectural remodeling in the liver. In this work we correlate changes in tight junctional morphometry induced by two-thirds hepatectomy with changes in biliary permeability assessed by sucrose and horseradish peroxidase permeation and by alterations in biliary outputs of anionic and cationic cholephilic probes. By freeze-fracture examination tight junctional strand counts, density and orientation parallel to canaliculi were all reduced 24 hr after two-thirds hepatectomy. Occasionally, strands were perpendicular to the canaliculi, creating an unobstructed communication between bile and intercellular spaces. These morphological changes correlated with increased sucrose and paracellular horseradish peroxidase access into bile, with reduced biliary outputs of low molecular weight and especially with cationic cholephilic probes. The data support an increased but still charge-selective permeability of the biliary tree, which was induced by two-thirds hepatectomy 24 hr before. Presumably, fixed intercellular connections (tight junctions and gap junctions) must be loosened or lysed to allow the architectural reorganization required by the hepatocellular regenerative process.

Animals↗