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PubMed1986

Thrombin-induced alterations in endothelial permeability.

Figure 15 summarizes the current understanding of mechanisms of endothelial permeability alterations induced with thrombin. If thrombin generation exceeds the antiprotease activity, thrombin results in clotting of fibrinogen and intravascular fibrin accumulation. Pulmonary neutrophil sequestration also occurs after fibrin deposition, and this is related to the degree and duration of fibrin sequestration. Neutrophil activation appears to be an essential requirement for the mediation of the pulmonary vascular injury. Thrombin-induced intravascular coagulation results in the generation of lipid mediators (LTB4 and HETEs), which may be involved in increasing endothelial permeability. The release of thrombin in higher concentrations during lysis of fibrin (sequence; see text) FIGURE 15. Hypothesis showing mechanisms of thrombin-induced increase in endothelial permeability to proteins. Thrombin may have direct effects on endothelial permeability, or thrombin induced fibrinogen clotting, activation of neutrophils, and the release of lipid metabolites that subsequently lead to an increase in endothelial permeability. clots may induce a direct formation of interendothelial "gaps." Therefore, the vascular injury induced by neutrophil activation and the formation of endothelial "gaps" induced directly by thrombin can both increase the endothelial permeability to proteins. Thrombin is an important mediator of increased endothelial permeability to macromolecules, and may participate in the inflammatory response. In this regard, thrombin may be similar to other mediators (such as histamine and serotonin) that have been previously documented to increase macromolecule transport across the endothelium. The implications of free thrombin in increasing endothelial permeability may be greater because thrombin not only has a direct effect on endothelial permeability, but also induces clotting of fibrinogen and the subsequent generation of mediators that activate neutrophils and that in turn can induce endothelial injury.

Actin Cytoskeleton↗

PubMed1970

Effect of some monovalent anions on chloride and sulphate permeability of human red cells.

1. The permeability of human red cells to (36)Cl(-) and to [(35)S]SO(4) (2-) was studied in the presence of various monovalent anions.2. A maximum decrease of anion permeability was found in a study of the steady-state exchange of (36)Cl in a medium containing 120 mM salicylate. The exchange had a half-time of 3 hr at 0 degrees C, a reduction of normal chloride permeability by a factor of 10(5). The activation energy of chloride exchange decreased from a value of 45 to 22 kcal/mole in the interval between 0 and 10 degrees C. Simultaneous determination of the permeability to potassium and chloride proved that salicylate induced a reversal of the normal selectivity of red cells at 0 degrees C (permeability coefficient P(K) of 3.5 x 10(-9) cm/sec to be compared with a P(Cl) of 2 x 10(-9) cm/sec).3. In contradistinction to the slow movement of (36)Cl, the exchange of [(14)C]salicylate was completed within 4 min, when red cells were suspended at 0 degrees C in the salicylate medium.4. A study of the sulphate permeability at 38 degrees C showed that the rate of steady-state exchange decreased, when chloride was replaced by lyotropic anions other than bromide. The sequence of the permeability decrease was: Cl(-) = Br(-) < I(-) < NO(3) < SCN(-) < salicylate, the same sequence which previously has been shown to increase the permeability to sodium and potassium. The activation energies of sulphate exchange were 32 kcal/mole (chloride medium), and 38 kcal/mole (thiocyanate medium).5. Sufficient data were obtained during the study to demonstrate that when equilibrium has been obtained, there is a good agreement between the values of (36)Cl (cell water)/(36)Cl (extracellular water) and of {[(35)S]SO(4) (cell water)/[(35)S]SO(4) (extracellular water)}((1/2)).6. It is concluded that the anion-induced changes of permeability are due to binding of anions to fixed cationic charges in the red cell membrane.

Activation Analysis↗

PubMed2003

Role of phospholipase C-beta in the modulation of epithelial tight junction permeability.

The results presented in this study establish an association between phospholipase C-beta (PLC-beta) and tight junction permeability across Madin-Darby canine kidney (MDCK) cell monolayers, an in vitro model for epithelial tissue. These results further show that PLC-beta modulates tight junction permeability by affecting actin filament organization. Hexadecylphosphocholine (HPC) inhibited PLC-beta and increased tight junction permeability in MDCK cells. Interestingly, the analogs of HPC, a series of alkylphosphocholines containing various lengths of linear alkyl chains, inhibited PLC-beta and increased tight junction permeability with a wide range of potency. The potency of alkylphosphocholines as enhancers of tight junction permeability significantly correlated (p < 0.05) with their potency as PLC-beta inhibitors. U73122, a steroid derivative that is structurally unrelated to alkylphosphocholines, inhibited PLC-beta and increased tight junction permeability with potencies that fit into the correlation observed for the alkylphosphocholine series. U73122 and HPC induced disorganization of actin filaments in MDCK cell monolayers. The potencies to cause disorganization of actin filaments were consistent with the potencies of these agents as inhibitors of PLC-beta and enhancers of tight junction permeability. Furthermore, ATP, an activator of PLC-beta, attenuated U73122-induced increase in tight junction permeability as well as disorganization of actin filaments. These results provide strong evidence that PLC-beta inhibition leads to increased tight junction permeability across MDCK cell monolayers through disorganization of actin filaments.

Animals↗

PubMed1995

Corneal epithelial permeability during extended wear of disposable contact lenses versus daily wear of soft contact lenses.

AIMS: The corneal epithelial permeability during extended wear of disposable contact lenses was compared with that during daily wear of soft contact lenses. The study was performed to verify whether the extended wear of disposable contact lenses would result in a higher permeability value than the daily wear of soft contact lenses. A higher permeability makes the cornea more vulnerable for bacterial infections and thus could explain the higher incidence of bacterial keratitis found in extended wear of disposable contact lenses in comparison with the daily wear of soft contact lenses. METHOD: The corneal epithelial permeability was determined by fluorophotometry in 33 healthy volunteers after the wear of soft, daily wear contact lenses for at least 6 months. Thereafter the determination was repeated in each volunteer after extended wear of disposable contact lenses for 1 month. The permeability in 34 healthy non-contact lens wearing volunteers was determined as a control. The permeability value was calculated from the amount of fluorescein that passed into the cornea after application by means of an eyebath. RESULTS: The mean permeability values after daily and extended wear were 0.032 nm/s and 0.031 nm/s, respectively. The values were not significantly different (Wilcoxon paired test p > 0.5). The mean permeability for the non-contact lens wearing controls was 0.042 nm/s. CONCLUSION: The results do not sustain the explanation that a difference in permeability value is the main cause of the increased incidence of keratitis during extended wear of disposable contact lenses in comparison with daily wear.

Adolescent↗

PubMed1992

Increased pulmonary and intestinal permeability in Crohn's disease.

We tested the hypothesis that an increased epithelial permeability may affect sites other than the intestine in patients with Crohn's disease by simultaneously evaluating their pulmonary and intestinal permeability. Pulmonary and intestinal permeability were measured by clearance of inhaled technetium-99m diethylene triamine pentacetate (99mTc-DTPA) and by urinary recovery of chromium-51 ethylene diamine tetracetate respectively in 22 patients with Crohn's disease. The half time clearance of 99mTc-DTPA from lung to blood (t1/2LB) was decreased--that is pulmonary permeability increased--in the whole group of patients with Crohn's disease as compared with 13 controls (median 45.5 minutes (8-160) v 85 minutes (34-130) (p less than 0.003)). When analysed separately only patients with active Crohn's disease (n = 15) had a decreased t1/2 lung to blood v controls (42 minutes (8-160) v 85 minutes (34-130) (p less than 0.0025)). Among patients with active Crohn's disease, six were studied again when their disease was quiescent and their t1/2 lung to blood did not differ significantly. The intestinal permeability was increased in the whole group of Crohn's disease patients as compared with 15 controls (5.25% (1.2-24) v 1.7% (0.65-5.75) (p less than 0.0002)). When analysed separately both patients with active and inactive Crohn's disease had increased intestinal permeability v controls (8.1% (1.6-24) and 3.5% (1.2.9.2) v 1.7% (0.65-5.75)) (p less than 0.0001, p = 0.05 respectively). Six patients with active Crohn's disease were studied again when their disease was quiescent and their intestinal permeability decreased significantly p less than 0.04). Pulmonary permeability was increased in patients with Crohn's disease but was not greatly influenced by Crohn's disease activity as opposed to intestinal permeability. The mechanism of this increase is unknown, but may be related in some patients to the presence of an alveolitis.

Adolescent↗

PubMed2000

Effect of endothelin and endothelin receptor blockade on capillary permeability in experimental pancreatitis.

BACKGROUND: Capillary leakage with fluid loss into the third space contributes to many of the early systemic complications in severe acute pancreatitis. There has been increasing interest in endothelin as one of the factors affecting capillary permeability. AIM: To elucidate further the role of endothelin in the development of capillary leakage in acute pancreatitis by investigating the effect of exogenous endothelin administration and endothelin receptor blockade in sham operated animals and two models of acute pancreatitis. METHODS: Determination of capillary permeability in the pancreas and colonic mucosa by quantifying extravasation of fluorescein labelled dextran using a novel computer assisted video image analysis system. RESULTS: Pancreatic and colonic capillary permeability increased stepwise from mild to severe acute pancreatitis. Endothelin increased pancreatic and colonic capillary permeability in healthy animals and animals with mild acute pancreatitis but had no additional adverse effect in severe acute pancreatitis. Endothelin receptor blockade decreased pancreatic capillary permeability in sham operated rats but had no effect on the colon. In mild and severe acute pancreatitis, endothelin receptor blockade stabilised increased capillary permeability in both the pancreas and colon. CONCLUSIONS: Endothelin plays an important role in mediating capillary permeability in the pancreas. In severe pancreatitis, it increases capillary permeability even outside the pancreas, thereby contributing to capillary leakage. Endothelin receptor blockade significantly reduces capillary permeability in acute pancreatitis both in and outside the pancreas, suggesting a therapeutic approach to counteract capillary leakage in severe acute pancreatitis.

Animals↗

PubMed1990

Regulation of Cl- permeability in normal and cystic fibrosis sweat duct cells.

Reabsorptive cells of the human sweat gland normally exhibit a high basal Cl- permeability but are markedly impermeable to Cl- in cystic fibrosis (CF). We examined the possibility that the reduced basal Cl- permeability of CF sweat duct cells in primary culture is due to a defective regulation of plasma membrane Cl- permeability by prostaglandin E2 (PGE2), which is endogenously produced by cultured sweat duct cells. The macroscopic Cl- permeabilities of normal and CF sweat duct cells were assessed using a halide-specific fluorescent dye, 6-methoxy-N-(3-sulfopropyl)quinolinium, in combination with fluorescence digital-imaging microscopy. The Cl- and Br- permeabilities of normal sweat duct cells were markedly reduced by inhibiting endogenous PGE2 production with indomethacin. This inhibition of Cl- permeability by indomethacin was largely reversed by the addition of PGE2 (10 nM to 1 microM), but not forskolin. Conversely, PGE2 failed to stimulate the low Cl- permeabilities of sweat duct cells cultured from CF subjects. Our results support the following conclusions: 1) a defective regulation of Cl- permeability in CF is a feature of reabsorptive as well as secretory epithelial cells, and 2) the nature of this regulatory defect extends beyond altered Cl- permeability regulation by adenosine 3',5'-cyclic monophosphate-dependent protein kinase.

Cell Membrane Permeability↗

PubMed1994

Determinants of apical membrane permeabilities of barrier epithelia.

Renal collecting duct and thick ascending limb, as well as stomach, exhibit strikingly low permeabilities to water and solutes. However, the apical membrane characteristics responsible for these unique permeabilities remain unknown. While the lipid composition of artificial membranes governs membrane permeability, exoplasmic and cytoplasmic leaflets of biological apical membranes exhibit striking asymmetries in lipid composition. This asymmetry, as well as the presence of membrane proteins, may be critical to barrier function. To determine the role of bulk lipid composition in apical membrane barrier function, we compared permeabilities to water (Pf), protons, ammonia, and several small nonelectrolytes of gastric apical membrane vesicles [native gastric vesicles (NGV)] and liposomes prepared from lipids quantitatively extracted from these vesicles [gastric lipid large unilamellar vesicles (LUV)]. Permeabilities were measured on a stopped-flow fluorimeter by monitoring self- or pH-sensitive quenching of entrapped carboxyfluorescein. NGV exhibited low Pf (2.8 +/- 0.3 x 10(-4) cm/s) while gastric lipid LUV Pf averaged 1.2 +/- 0.1 x 10(-3) cm/s, a fourfold increase compared with the value in NGV. Gastric lipid LUV also demonstrated higher permeabilities to protons, ammonia, propylene glycol, butyramide, ethanolamine, and acetamide compared with values in NGV. In contrast, gastric lipid LUV exhibited the same or lower permeabilities to urea, glycerol, and ammonia compared with values in NGV. We conclude that lipid composition alone can reconstitute membrane permeabilities to some, but not all, molecules. These results indicate that bilayer asymmetry may be required for the unique permeability of "water-tight" apical membranes and reveal different barrier mechanisms for water and protons, as opposed to ammonia, urea, and glycerol.

Cell Membrane Permeability↗

PubMed1997

Nitric oxide enhances hydrogen peroxide-mediated endothelial permeability in vitro.

The objective of this study was to evaluate the effects of nitric oxide (NO) on H2O2-mediated endothelial permeability. H2O2 (0.1 mM) increased permeability at 90 min to 298% of baseline. Spermine NONOate (SNO), an NO donor, at 0.1 or 1 mM did not alter permeability. However, 0.1 mM H2O2 + 1 mM SNO increased permeability to 764%, twice that of 0.1 mM H2O2 alone. These treatments were not directly toxic to endothelial cells. This NO effect was concentration dependent, inasmuch as 0.1 mM SNO did not significantly change H2O2-mediated permeability. The NO-enhanced, H2O2-dependent permeability required the simultaneous presence of NO and H2O2, inasmuch as preincubation with SNO for 30 min followed by 0.1 mM H2O2 did not alter permeability. Staining of endothelial junctions showed widening of the intercellular space only in junctions of cells exposed to H2O2 (0.1 mM) + SNO (1 mM). Furthermore, NO did not affect H2O2 metabolism by endothelial cells but significantly depleted intracellular glutathione. This reduction of cell glutathione produced by NO exposure recovered 15-30 min after removal of the NO donor. NO-enhanced permeability was completely blocked by methionine (1 mM), a scavenger of reactive oxygen species, and by the iron chelator desferrioxamine (0.1 mM). These results suggest that NO may exacerbate the effects of H2O2-dependent increase in endothelial monolayer permeability via the iron-catalyzed formation of reactive oxygen metabolites.

Animals↗

PubMed1993

Duodenal mucosal alkaline secretion, permeability, and blood flow.

The relationship between duodenal mucosal alkaline secretion, permeability, and blood flow was examined in anesthetized rats. Duodenum was perfused with saline, and rate of luminal alkalinization (LA), mucosal permeability (clearance of 51Cr-EDTA from blood to lumen), effluent volume, mean arterial blood pressure (MABP), and blood flow (laser-Doppler flowmetry) were determined. Infusion of vasoactive intestinal polypeptide (VIP, 13.5 micrograms.kg-1 x h-1 i.v.) increased LA and fluid secretion but decreased MABP and mucosal permeability. The concentration of base in the secreted fluid was 45 mM. Systemic infusion of VIP (2.5 micrograms.kg-1 x h-1) increased LA and fluid secretion; the HCO3- concentration in secreted fluid was 86 mM. The lower VIP dose affected neither blood flow nor mucosal permeability. Both intravenous (10 mg/kg + 3 mg.kg-1 x h-1) and intraluminal (3 x 10(-3) M) N omega-nitro-L-arginine (L-NNA) increased LA and effluent volume; the HCO3- concentration in the secreted fluid was 38 and 44 mM, respectively. Intravenous, but not intraluminal, L-NNA increased mucosal permeability and decreased blood flow. Reduction of arterial blood pressure by blood withdrawal or by injection of prazosin (50 micrograms/kg i.v.) or hexamethonium (20 mg/kg i.v.) decreased LA and mucosal permeability. Prazosin decreased blood flow, whereas hexamethonium slightly increased blood flow. We conclude that NO may be an inhibitory regulator of LA and that both L-NNA and VIP increase LA via stimulation of active HCO3- transport. VIP probably increases HCO3- and fluid secretion by two separate ion transport mechanisms. No causal relationship exists between LA and blood flow, between LA and mucosal permeability, or between mucosal permeability and blood flow. A positive linear correlation exists between MABP and mucosal permeability, suggesting that marked changes of MABP may influence permeation of small water-soluble solutes across duodenal mucosa.

Animals↗

PubMed2002

Tumor necrosis factor-alpha-induced leukocyte adhesion and microvessel permeability.

The objective of this study was to investigate whether leukocyte adhesion and/or emigration are critical steps in increased microvessel permeability during acute inflammation. To conduct this study, we combined autologous blood perfusion with a single microvessel perfusion technique, which allows microvessel permeability to be measured precisely after the endothelium has interacted with blood-borne stimuli. Experiments were carried out in intact venular microvessels in rat mesenteries. Firm attachment of leukocytes to endothelial cells was induced by intravenous injection of TNF-alpha (3.5 microg/kg) and resuming autoperfusion in a precannulated microvessel. Leukocyte emigration was facilitated by superfusion of formyl-Met-Leu-Phe-OH. Microvessel permeability was measured as hydraulic conductivity (L(p)) or the solute permeability coefficient to tetramethylrhodamine isothiocyanate-labeled alpha-lactalbumin before and after leukocyte adhesion and emigration in individually perfused microvessels. We found that perfusion of a microvessel with TNF-alpha did not affect basal microvessel permeability, but intravenous injection of TNF-alpha caused significant leukocyte adhesion. However, the significant leukocyte adhesion and emigration did not cause corresponding increases in either L(p) or solute permeability. Thus our results suggest that leukocyte adhesion and emigration do not necessarily increase microvessel permeability and the mechanisms that regulate the adhesion process act independently from mechanisms that regulate permeability. In addition, silver staining of endothelial boundaries demonstrated that leukocytes preferentially adhere at the junctions of endothelial cells. The appearance of the silver lines indicates that the TNF-alpha-induced firm adhesion of leukocyte to microvessel walls did not involve apparent changes in the junctional structure of endothelial cells, which is consistent with the results of permeability measurements.

Animals↗

PubMed1992

Transient venular permeability increase and endothelial gap formation induced by histamine.

Histamine is known to increase permeability of venules and to cause formation of gaps between endothelial cells. The permeability increase is transient, lasting only a few minutes during continuous histamine application. In this study, three series of experiments were conducted to test the hypothesis that the transient permeability increase is due to transient formation of endothelial gaps. First, the time course of permeability changes to alpha-lactalbumin during 15 min of 10(-3) M histamine suffusion was determined on single venules in the rat mesentery. With histamine application, permeability increased initially, peaked with an average of fivefold increase around the 3rd min, and then declined toward control. Second, the temporal development of endothelial gaps during histamine treatment was studied with electron microscopy. The fraction of gaps among all junctions increased from 2% at control to 26.5% at 3 min and then decreased toward control. Finally, gap morphology data were obtained from the individual venules whose permeability response to a given period of histamine treatment had been recorded. The temporal development of the gaps was mirrored by that of permeability. Because both permeability and endothelial gaps followed similar developmental patterns during histamine treatment, the result of our study supports the hypothesis that the histamine-induced transient permeability increase is due to transient formation of endothelial gaps.

Animals↗

PubMed1997

Dual role of cGMP in modulation of macromolecule permeability of aortic endothelial cells.

The effect of guanosine 3',5'-cyclic monophosphate (cGMP) on cytosolic Ca2+ dynamics and associated alterations in macromolecule permeability was investigated in cultured monolayers of aortic endothelial cells. Addition of the membrane-permeable cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 5 x 10(-4)M) or activators of the soluble (3-morpholinosydnonimine, 10(-5) M) or the particulate guanylyl cyclase (atrial natriuretic peptide, 10(-7) M) to unstimulated monolayers led to a decrease in permeability (8-BreGMP: 62 +/- 8% of control) without affecting low basal cytosolic Ca2+ concentration ([Ca2+]i, 87 +/- 8 nM). In contrast, under conditions of elevated [Ca2+]i (503 +/- 95 nM) and increased permeability (155 +/- 7% of control) induced by 10(-6) M ionomycin, 8-BrcGMP, 3-morpholinosydnonimine, or atrial natriuretic peptide provoked a further increase in permeability (8-BrcGMP: 255 +/- 27%). These agents failed to increase permeability when added before or after the ionomycin-triggered transitory rise in [Ca2+]i. The increase in permeability in response to 8-BrcGMP was due to a secondary further rise in [Ca2+]i (758 +/- 87 nM), which was abolished in the absence of extracellular Ca2+, indicating influx of exogenous Ca2+ as the cause. Changes in [Ca2+]i and permeability were inhibited, in the presence of the Rp diastereomer of 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphothioate (2 x 10(-5) M), an inhibitor of the cGMP-dependent protein kinase. These findings show that, depending on [Ca2+]i, cGMP can play opposite roles in endothelial permeability in one and the same cell preparation.

Animals↗

PubMed1999

ATP reduces macromolecule permeability of endothelial monolayers despite increasing [Ca2+]i.

We investigated the relationship between the ATP-evoked rise of cytosolic Ca2+ concentration ([Ca2+]i) and barrier function in porcine aortic endothelial monolayers. ATP (0.01-100 microM) induced a transient rise of [Ca2+]i and reduced permeability in a concentration-dependent manner. In contrast, the Ca2+ ionophore ionomycin (1 microM) elicited a rise in [Ca2+]i comparable to that induced by ATP (10 microM), but it increased permeability. For the reduction of permeability, nucleotides were found to be in the following order of potency: ATP = ATPgammaS > ADP = UTP. Blockade of adenosine receptors by 8-phenyltheophylline (10 microM) did not affect ATP (10 microM)-induced reduction of permeability. ATP reduced permeability even in endothelial monolayers that had been loaded with the Ca2+ chelator BAPTA to prevent the rise in [Ca2+]i. U-73122 (1 microM), an inhibitor of phospholipase C (PLC), completely abolished the effect of ATP (10 microM) on permeability. It also abolished the translocation of protein kinase C (PKC) in response to ATP, which could also be achieved by the PKC inhibitors Gö-6976 (100 nM) or bisindolylmaleimide I (1 microM). In the presence of PKC inhibitors, however, the permeability effect of ATP was not affected. The presence of inhibitors of adenylate or guanylate cyclase (50 microM SQ-22536 or 20 microM ODQ) prevented changes in cyclic nucleotides but did not affect the permeability effects of ATP. The study shows that ATP reduces macromolecule permeability via a PLC-mediated mechanism that is independent of the concomitant effects of ATP on cytosolic Ca2+, cyclic nucleotides, or PKC.

Adenosine Triphosphate↗

PubMed2001

Evaluation of basement membrane degradation during TNF-alpha-induced increase in epithelial permeability.

We evaluated whether tumor necrosis factor (TNF)-alpha induces an increase in permeability of an alveolar epithelial monolayer via gelatinase secretion and basement membrane degradation. Gelatinase secretion and epithelial permeability to radiolabeled albumin under unstimulated and TNF-alpha-stimulated conditions of an A549 human epithelial cell line were evaluated in vitro. TNF-alpha induced both upregulation of a 92-kDa gelatinolytic activity (pro form in cell supernatant and activated form in extracellular matrix) and an increase in the epithelial permeability coefficient compared with the unstimulated condition (control: 1.34 +/- 0.04 x 10(-6) cm/s; 1 microg/ml TNF-alpha: 1.47 +/- 0.05 x 10(-6) cm/s, P < 0.05). The permeability increase in the TNF-alpha-stimulated condition involved both paracellular permeability, with gap formation visualized by actin cytoskeleton staining, and basement membrane permeability, with an increase in the basement membrane permeability coefficient (determined after cell removal; control: 2.58 +/- 0.07 x 10(-6) cm/s; 1 microg/ml TNF-alpha: 2.82 +/- 0.02.10(-6) x cm/s, P < 0.05). Because addition of gelatinase inhibitors [tissue inhibitor of metalloproteinase (TIMP)-1 or BB-3103] to cell supernatants failed to inhibit the permeability increase, the gelatinase-inhibitor balance in the cellular microenvironment was further evaluated by cell culture on a radiolabeled collagen matrix. In the unstimulated condition, spontaneous collagenolytic activity inhibited by addition to the matrix of 1 microg/ml TIMP-1 or 10(-6) M BB-3103 was found. TNF-alpha failed to increase this collagenolytic activity because it was associated with dose-dependent upregulation of TIMP-1 secretion by alveolar epithelial cells. In conclusion, induction by TNF-alpha of upregulation of both the 92-kDa gelatinase and its inhibitor TIMP-1 results in maintenance of the gelatinase-inhibitor balance, indicating that basement membrane degradation does not mediate the TNF-alpha-induced increase in alveolar epithelial monolayer permeability.

Basement Membrane↗

PubMed2001

Intestinal permeability is reduced and IL-10 levels are increased in septic IL-6 knockout mice.

Sepsis is associated with increased intestinal permeability, but mediators and mechanisms are not fully understood. We examined the role of interleukin (IL)-6 and IL-10 in sepsis-induced increase in intestinal permeability. Intestinal permeability was measured in IL-6 knockout (IL-6 -/-) and wild-type (IL-6 +/+) mice 16 h after induction of sepsis by cecal ligation and puncture or sham operation. In other experiments, mice or intestinal segments incubated in Ussing chambers were treated with IL-6 or IL-10. Intestinal permeability was assessed by determining the transmucosal transport of the 4.4-kDa marker fluorescein isothiocyanate conjugated dextran and the 40-kDa horseradish peroxidase. Intestinal permeability for both markers was increased in septic IL-6 +/+ mice but not in septic IL-6 -/- mice. Treatment of nonseptic mice or of intestinal segments in Ussing chambers with IL-6 did not influence intestinal permeability. Plasma IL-10 levels were increased in septic IL-6 -/- mice, and treatment of septic mice with IL-10 resulted in reduced intestinal permeability. Increased intestinal permeability during sepsis may be regulated by an interaction between IL-6 and IL-10. Treatment with IL-10 may prevent the increase in mucosal permeability during sepsis.

Animals↗

PubMed2005

Selective permeability barrier to urea in shark rectal gland.

Elasmobranchs such as the dogfish shark Squalus acanthius achieve osmotic homeostasis by maintaining urea concentrations in the 300- to 400-mM range, thus offsetting to some degree ambient marine osmolalities of 900-1,000 mosmol/kgH(2)O. These creatures also maintain salt balance without losing urea by secreting a NaCl-rich (500 mM) and urea-poor (18 mM) fluid from the rectal gland that is isotonic with the plasma. The composition of the rectal gland fluid suggests that its epithelial cells are permeable to water and not to urea. Because previous work showed that lipid bilayers that permit water flux do not block flux of urea, we reasoned that the plasma membranes of rectal gland epithelial cells must either have aquaporin water channels or must have some selective barrier to urea flux. We therefore isolated apical and basolateral membranes from shark rectal glands and determined their permeabilities to water and urea. Apical membrane fractions were markedly enriched for Na-K-2Cl cotransporter, whereas basolateral membrane fractions were enriched for Na-K-ATPase. Basolateral membrane osmotic water permeability (P(f)) averaged 4.3 +/- 1.3 x 10(-3) cm/s, whereas urea permeability averaged 4.2 +/- 0.8 x 10(-7) cm/s. The activation energy for water flow averaged 16.4 kcal/mol. Apical membrane P(f) averaged 7.5 +/- 1.6 x 10(-4) cm/s, and urea permeability averaged 2.2 +/- 0.4 x 10(-7) cm/s, with an average activation energy for water flow of 18.6 kcal/mol. The relatively low water permeabilities and high activation energies argue strongly against water flux via aquaporins. Comparison of membrane water and urea permeabilities with those of artificial liposomes and other isolated biological membranes indicates that the basolateral membrane urea permeability is fivefold lower than would be anticipated for its water permeability. These results indicate that the rectal gland maintains a selective barrier to urea in its basolateral membranes.

Animals↗

PubMed1982

Permeability and channel structure of reptilian skin.

A study of the permeability of shed epidermis from some terrestrial and freshwater snakes was conducted. Permeability to Br, Na, and K ions was very low and showed a higher influx than efflux in most cases. Permeability to the smaller water molecule was much greater, and in contrast efflux was higher than influx. Skins from aquatic snakes with larger water permeabilities also showed greater permeabilities to Na and K. The highly aquatic Regina septemvittata has the most permeable skin of any snake. Ethanol fluxes were higher than expected for a tracer of its size, perhaps due to its solubility in lipid. Na fluxes through whole live skins of Nerodia cyclopion floridana in vitro were not significantly different from those of the shed skin alone. Isolated hinge regions showed complete water impermeability, suggesting that channels through the skin are located only in the scale region. Dermal water efflux into dry air was considerably less than water-to-water efflux. Lipid extraction increased permeability markedly and eliminated the asymmetry of water and ion fluxes. Lipid replacement with linoleic acid restored half of the water impermeability lost during extraction. Protein extraction did not significantly increase membrane permeability but did eliminate the permeability difference between dry and hydrated skins. Two sizes of lipid-lined channels extending through a protein matrix are suggested as a possible model for snake skin. The diameter of the channels apparently varies in relation to the differing water, Na, and Cl concentrations on opposite sides of the skin, but the mechanism of this adjustment is unknown.

Animals↗