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PubMed2000

pH and calcium regulate the water permeability of aquaporin 0.

Aquaporins increase the water permeability in many cell types across many species. We investigated the effects of external pH and Ca(2+) on water permeability of Xenopus oocytes injected with aquaporin cRNA by measuring the rate of swelling in hypotonic solutions. Lowering pH to 6.5 increased the water permeability of aquaporin (AQP0) 3.4 +/- 0.4-fold. Diethylpyrocarbonate pretreatment increased water permeability 4.2 +/- 0.5-fold and abolished pH sensitivity, suggesting that the pH regulation is mediated by an external histidine. Lowering Ca(2+) increased water permeability 4.1 +/- 0. 4-fold. The effects of Ca(2+) and pH each required the presence of histidine 40, indicating a critical role of this amino acid in facilitating the modulation of water permeability. Clamping intracellular Ca(2+) at high or low values abolished sensitivity to external Ca(2+), suggesting that Ca(2+) acts at an internal site. Three different calmodulin inhibitors each increased AQP0 water permeability, suggesting that Ca(2+) may act through calmodulin. None of the above altered the water permeability induced by AQP1 or AQP4. Because the greatest change in AQP0 water permeability is in the normal pH range found in the lens (7.2-6.5), this paper provides evidence for regulation of an aquaporin by pH under physiological conditions.

Amino Acid Sequence↗
PubMed1997

Effect of tear lubricating solutions on in vivo corneal epithelial permeability.

PURPOSE: The rabbit corneal epithelial permeability was measured noninvasively following exposure to commercially available tear lubricating solutions. METHODS: The normal unanesthetized rabbit's corneal surface was either bathed in the tear lubricating solution for 5 min or received multiple applications of 2 drops per 30 min for 6 h for one or five days. The corneal epithelial permeability to carboxyfluorescein after a 5-min bath was measured with the Fluorotron Master. Fifteen commercially available tear preparations were tested. RESULTS: The baseline corneal epithelial permeability was 0.0455 +/- 0.0114 nm/s. The epithelial permeability values for the corneas bathed for 5 min in control solution (BSSplus) was 0.0798 +/- 0.0074 nm/s, in the preservative-free tear lubricating solutions the range was 0.512 to 0.542 nm/s, and in the preserved tear lubricating solutions the range was 0.3518 to 11.8873 nm/s. The preservative-free tear lubricating solutions had epithelial cell permeabilities up to 6 times greater than the control solution. Whereas, the preserved tear lubricating solutions had epithelial cell permeabilities up to 149 times greater than the control solution. Multiple applications of the tear lubricating solutions for 5 days were less damaging to the epithelial permeability than the 5 min bath applications. The resulting epithelial permeabilities were up to 2 fold greater than the control with the corresponding preservative-free solution and up to 29 fold greater than control with the corresponding preserved solution. CONCLUSION: An extended exposure of 5 min to various tear lubricating solutions demonstrated significant differences in epithelial cell permeability between preserved solutions and unpreserved solutions, whereas the multiple drop application technique demonstrated all of the preservative-free solutions and some of the preserved solutions to be insignificantly different from the control solution.

Animals↗
PubMed2000

Permeability of chemical delivery systems across rabbit corneal (SIRC) cell line and isolated corneas: a comparative study.

The purpose of this study was to investigate the corneal permeability of phenylephrone chemical delivery systems (CDS) across isolated cornea and to evaluate the utility of the SIRC cell line (epithelial cells originating from rabbit cornea) as an in vitro model for predicting the ocular permeability. The effect of benzalkonium chloride (BAC) on the drug permeability through SIRC cell layers was also studied. The transport of phenylephrone CDS across the isolated cornea of the albino rabbit was measured at various pH values using a two-chamber glass diffusion cell, and the results were compared with the reported permeability values across SIRC cells of rabbit origin. Corneal membranes showed lower flux values for compounds, especially for hydrophilic compounds, than the SIRC cell line. A significant correlation was observed between the permeability coefficients through corneal membranes and SIRC cells. When the pH of the transport medium was increased, the permeability coefficients increased and lag times decreased in both in vitro models. Furthermore, both in vitro models showed significant correlation between permeability coefficients and lipophilicities of the drugs. The three esters, having higher lipophilic characteristics, showed higher permeability than phenylephrine HCl. The phenylacetyl ester of phenylephrone showed a three-fold increase in penetration across SIRC cell layers in the presence of 0.01% BAC. These results suggest that the use of SIRC cell layers can reasonably predict the permeability of ophthalmic drugs across corneal membranes.

Animals↗
PubMed1993

Thrombin receptor peptide inhibits thrombin-induced increase in endothelial permeability by receptor desensitization.

Thrombin, a potent activator of cellular responses, proteolytically cleaves, and thereby activates its receptor. In the present study, we compared the effects of the thrombin receptor 14-amino acid peptide (TRP-14; SFLLRNPNDKYEPF), which comprises the NH2 terminus after cleavage of the thrombin receptor, and of the native alpha-thrombin on endothelial monolayer permeability. Addition of TRP-14 (1-200 microM) to bovine pulmonary artery endothelial cells increased [Ca2+]i in a dose-dependent manner. The peak increase in [Ca2+]i in response to 100 microM TRP-14 or 0.1 microM alpha-thrombin was similar (i.e., 931 +/- 74 nM and 1032 +/- 80 nM, respectively), which was followed by a slow decrease with t1/2 values of 0.73 and 0.61 min, respectively. Extracellular Ca2+ chelation with 5 mM EGTA abolished the sustained increases in [Ca2+]i induced by either TRP-14 or alpha-thrombin. alpha-thrombin (0.1 microM) increased transendothelial [125I]albumin permeability, whereas TRP-14 (1-100 microM) had no effect. Coincubation of 100 microM TRP-14 with 1 microM DIP-alpha-thrombin also did not increase permeability over control values. Stimulation of BPAEC with 0.1 microM alpha-thrombin induced translocation of protein kinase C (PKC) from the cytosol to the plasma membrane indicative of PKC activation, whereas TRP-14 had no effect at any concentration. TRP-14 at 100 microM desensitized BPAEC to thrombin-induced increases in [Ca2+]i and transendothelial permeability. The Ca2+ desensitization was reversed after approximately 60 min, and this recovery paralleled the recovery of the permeability response. These findings indicate that the TRP-14-induced Ca2+ mobilization in the absence of PKC activation is insufficient to increase endothelial permeability. In contrast, the increase in endothelial permeability after alpha-thrombin occurred in conjunction with Ca2+ mobilization as well as PKC activation. TRP-14 pretreatment prevented the alpha-thrombin-induced increase in endothelial permeability secondary to desensitization of the Ca2+ signal. The results suggest that combined cytosolic Ca2+ mobilization mediated by TRP-14 and PKC activation mediated by a TRP-14-independent pathway are dual signals responsible for the thrombin-induced increase in vascular endothelial permeability.

Amino Acid Sequence↗
PubMed1983

Urea permeability of human red cells.

The rate of unidirectional [14C]urea efflux from human red cells was determined in the self-exchange and net efflux modes with the continuous flow tube method. Self-exchange flux was saturable and followed simple Michaelis-Menten kinetics. At 38 degrees C the maximal self-exchange flux was 1.3 X 10(-7) mol cm-2 s-1, and the urea concentration for half-maximal flux, K1/2, was 396 mM. At 25 degrees C the maximal self-exchange flux decreased to 8.2 X 10(-8) mol cm-2 s-1, and K1/2 to 334 mM. The concentration-dependent urea permeability coefficient was 3 X 10(-4) cm s-1 at 1 mM and 8 X 10(-5) cm s-1 at 800 mM (25 degrees C). The latter value is consonant with previous volumetric determinations of urea permeability. Urea transport was inhibited competitively by thiourea; the half-inhibition constant, Ki, was 17 mM at 38 degrees C and 13 mM at 25 degrees C. Treatment with 1 mM p-chloromercuribenzosulfonate inhibited urea permeability by 92%. Phloretin reduced urea permeability further (greater than 97%) to a "ground" permeability of approximately 10(-6) cm s-1 (25 degrees C). This residual permeability is probably due to urea permeating the hydrophobic core of the membrane by simple diffusion. The apparent activation energy, EA, of urea transport after maximal inhibition was 59 kJ mol-1, whereas in control cells EA was 34 kJ mol-1 at 1 M and 12 kJ mol-1 at 1 mM urea. In net efflux experiments with no extracellular urea, the permeability coefficient remained constantly high, independent of a variation of intracellular urea between 1 and 500 mM, which indicates that the urea transport system is asymmetric. It is concluded that urea permeability above the ground permeability is due to facilitate diffusion and not to diffusion through nonspecific leak pathways as suggested previously.

Biological Transport↗
PubMed1995

Permeability of the blood-retinal and blood-aqueous barriers in galactose-fed rats.

Blood-retinal barrier (BRB) and blood-aqueous barrier (BAB) permeability were assessed by various methods to clarify conflicting reports on whether blood-retinal barrier permeability changes occur in diabetic and galactose-fed rats and to assess the potential role of aldose reductase in this process. Different molecular weight probes were utilized in rats fed for 7-11 months either a normal diet or a diet containing 50% galactose with/without the aldose reductase inhibitor AI1576 or Ponalrestat. BRB and BAB were assessed through radiolabelled sucrose permeability studies in eyes where the anterior segment was frozen during dissection compared to eyes where the anterior segments were not frozen and by quantitative autoradiography. In addition, histological studies using Evans Blue dye, microperoxidase and horseradish peroxidase were conducted. In untreated galactose-fed rats a 4-fold increase in the mean permeability surface area product (PA) to sucrose at the BRB was observed when the aqueous humor was not frozen during retinal dissection. However, no increase in the mean PA to sucrose was observed when the aqueous humor of similar eyes was frozen during dissection. Similarly, no retinal vessel permeability increase was observed by either quantitative autoradiography of [3H]-sucrose after 15 minutes of circulation or histological studies with microperoxidase, horseradish peroxidase or Evans Blue dye. Examination of the BAB revealed an increase in the permeability of iris vessels but not the ciliary body in galactose-fed rats which was reduced by treatment with the aldose reductase inhibitor AI1576. These data indicate that while BRB permeability is not increased in galactose-fed rats, BRB permeability measurements with isotopes are subject to possible contamination from the aqueous humor in untreated galactose-fed rats, which can result in false observations of increased BRB permeability.

Aldehyde Reductase↗
PubMed1990

Characterization of Sertoli cells cultured in the bicameral chamber system: relationship between formation of permeability barriers and polarized secretion of transferrin.

Sertoli cells from immature rats (18 days old) were cultured on Millipore filters impregnated with reconstituted basement membrane in bicameral chambers. Three types of cultures were obtained: 1) confluent monolayer cultures that formed a permeability barrier (impermeable), 2) confluent monolayer cultures that did not form a permeability barrier (permeable), and 3) subconfluent cultures (permeable). The relationships among fluid equilibrium, electrical resistance, and [3H]inulin transport between the apical and basal reservoirs of the chambers were examined. An impermeable confluent monolayer is defined when the cells of the Sertoli cell epithelial sheet are able to prevent hydrodynamic equilibration of fluid levels between the apical and basal reservoirs of a bicameral chamber. That is, a permeability barrier is present between the two sides of the chamber when fluid levels (volumes) do not change. In the impermeable confluent Sertoli cell monolayers, 7.5 +/- 0.6% of added [3H]inulin diffused across the monolayer during a 6-h collection period versus 13.7 +/- 0.5% in permeable cultures. Conversely, the electrical resistance was higher in the impermeable monolayers (41-71 ohm.cm2) than in the permeable layers (less than 33 ohm.cm2). A reciprocal linear relationship (Y = -4.68(X) + 91.50, r = 0.808) exists between inulin flux and electrical resistance, and this relationship is a function of cell density. Transferrin (Tf) was one of a few proteins detected in the basal medium of bicameral chambers, whereas most de novo synthesized proteins were secreted into the apical reservoir of the chamber. No significant differences in the total amount of Tf secreted by impermeable or permeable monolayers of Sertoli cells were observed. However, the Sertoli cell secretion ratios (apical/basal) of Tf during a 15-20-h collection period were 2.03 and 1.57 for impermeable monolayers plated at 2.4 x 10(6) and 3.6 x 10(6) cells/well, respectively, but less than 1.0 in permeable layers of cells. When fewer than 2 x 10(6) Sertoli cells were plated, the apical/basal polarity of Tf secretion declined to below 1 in a 24-h culture period, even though those chambers contained impermeable monolayers (recognized by the lack of hydrodynamic equilibrium). These results indicate that polarized secretion by Sertoli cells is dependent on (1) plating density and (2) formation of an impermeable epithelial sheet.

Animals↗
PubMed2003

VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor.

Vascular endothelial growth factor/vascular permeability factor (VEGF) has been implicated in blood/tissue barrier dysfunctions associated with pathological angiogenesis, but the mechanisms of VEGF-induced permeability increase are poorly understood. Here, the role of VEGF-induced extracellular proteolytic activities on the endothelial cell permeability increase is evaluated. Confluent monolayers of bovine retinal microvascular endothelial (BRE) cells grown on porous membrane were treated with VEGF or urokinase plasminogen activator (uPA), and permeability changes were analyzed. uPA-induced permeability was rapid and sustained, but VEGF-induced permeability showed a biphasic pattern: a rapid and transient phase (1-2 h) followed by delayed and sustained phase (6-24 h). The delayed, but not the early phase of VEGF-induced permeability, was blocked by anti-uPA or anti-uPAR (uPA receptor) antibodies and was accompanied by reduced transendothelial electrical resistance, indicating the paracellular route of permeability. Confocal microscopy and Western blotting showed that VEGF treatment increased free cytosolic beta-catenin, which was followed by beta-catenin nuclear translocation, upregulation of uPAR, and downregulation of occludin. Membrane-bound occludin was released immediately after uPA treatment, but with a long delay after VEGF treatment, suggesting a requirement for uPAR gene expression. In conclusion, VEGF induces a sustained paracellular permeability in capillary endothelial cells that is mediated by activation of the uPA/uPAR system.

Animals↗
PubMed1999

Low-dose prostacyclin is superior to terbutaline and aminophylline in reducing capillary permeability in cat skeletal muscle in vivo.

OBJECTIVE: To analyze and compare the capillary permeability-reducing effects of prostacyclin, terbutaline, and aminophylline. DESIGN: A prospective, experimental study. SETTING: A university laboratory. SUBJECTS: Fourteen adult, anesthetized cats. INTERVENTIONS: The study was performed on an autoperfused calf muscle preparation enclosed in a plethysmograph, with continuous recordings of tissue volume, arterial and venous blood pressures, and blood flow. The capillary filtration coefficient was used as a measure of capillary hydraulic permeability, and measured at different doses of intravenous infusions of prostacyclin, terbutaline, and aminophylline. These analyses were made from normal and from raised permeability levels, the latter by prior and simultaneous infusion of tumor necrosis factor-a (TNF-a) or histamine. All three of the drugs analyzed were given at low doses, without vasodilator effect, and at doses with a clear vasodilator effect. MAIN RESULTS: Prostacyclin infusion reduced capillary permeability to a value of about 25% below the initial control value, and this level was reached both from normal and increased permeability levels. The maximal reduction level was obtained at a low nonvasodilator dose of 2 ng/kg/min. Terbutaline and aminophylline had no significant effect on capillary filtration coefficient when tested from the initial control permeability level. From a TNF-alpha-raised permeability level (about 50% above control) and from a histamine-raised permeability level (about 60% above control), both drugs induced small reductions in the capillary filtration coefficient. CONCLUSION: Low-dose prostacyclin effectively reduces hydraulic capillary permeability in cat skeletal muscle and is superior to terbutaline and aminophylline.

Adrenergic beta-Agonists↗
PubMed2002

Tumor necrosis factor-alpha and interleukin-1beta mediate endothelial permeability induced by lipopolysaccharide-stimulated whole blood.

OBJECTIVE: To investigate the role of endotoxin-induced inflammatory mediators in blood on the permeability of endothelial monolayers. DESIGN: Whole blood of healthy volunteers was treated with bacterial lipopolysaccharide (Escherichia coli, B55:05), and the resultant plasma was added to human umbilical venular endothelial cells (HUVEC) cultured on semipermeable membrane inserts (Transwells). SETTING: University hospital laboratory. SUBJECTS: Whole blood of healthy volunteers. INTERVENTIONS: Donor plasma was treated with excess antibodies against either tumor necrosis factor-alpha, interleukin-1beta, or both, before the incubation on HUVEC. MEASUREMENTS AND MAIN RESULTS: The permeability of HUVEC monolayers to fluorescent-labeled albumin and dextran was measured over a 6-hr period, after removal of the stimulus. The production of tumor necrosis factor-alpha and interleukin-1beta in lipopolysaccharide-treated whole blood was determined by radioimmunoassay. Individually, lipopolysaccharide (10 microg/mL), tumor necrosis factor-alpha (10 ng/mL), and interleukin-1beta (50 ng/mL) all increased endothelial permeability by about 2.5-fold. A much larger increase could be achieved by preincubation of lipopolysaccharide (10 microg/mL) in whole blood: the resultant plasma induced a ten-fold increase of the permeability. The permeability response after preincubation of lipopolysaccharide in whole blood was time- and dose-dependent. Moreover, this treatment increased the sensitivity of endothelial monolayers to lipopolysaccharide by a factor of several thousand-fold: Whereas high doses of lipopolysaccharide were required for direct stimulation of the permeability, picomolar amounts of lipopolysaccharide in whole blood induced a similar increase. Significant amounts of tumor necrosis factor-alpha and interleukin-1beta were produced in blood at similar doses of lipopolysaccharide. The addition of antibodies against tumor necrosis factor-alpha or interleukin-1beta to plasma partially but significantly abrogated the permeability increase. However, a complete inhibition could be achieved by the simultaneous addition of anti-tumor necrosis factor-alpha and anti-interleukin-1beta to plasma. CONCLUSIONS: Although lipopolysaccharide is capable of directly inducing endothelial permeability, blood-borne tumor necrosis factor-alpha and interleukin-1beta mediate lipopolysaccharide-induced endothelial permeability at low endotoxin concentrations. These findings support the idea that multifactorial inhibition of inflammatory mediators may improve survival in septic patients.

Capillary Permeability↗
PubMed1982

Permeability of different experimental brain tumor models to horseradish peroxidase.

The permeability of different brain tumor models to horseradish peroxidase (HRP) was examined by determining the fraction of tumor that contained HRP after intravenous administration. The intracerebral tumor models studied were Avian Sarcoma Virus (ASV)-induced tumors and tumors from transplanted RG-2, S69-C1-5, and 9L cell lines. The average fraction of RG-2 tumors permeable to HRP was .95; of S69-C1-5 tumors, .699; of ASV-induced tumors. .63; and of 9L tumors, .52. Except for the RG-2 tumors, there was considerable regional variation in HRP permeability, which was most marked in the ASV-induced tumors. In ASV-induced tumors, HRP permeability did not correlate with tumor histological classification, size, or anatomic location within the brain. The subcutaneous tumor models studied were RG-2-, S69-C1-5, and 9L-transplanted tumors in rats, and human glioblastoma cell lines transplanted into nude mice. All were completely permeable to HRP. These results indicate that significant differences in permeability to HRP exist among brain tumor models when the tumors are intracerebral, and that all subcutaneous tumors from transplanted glial cell lines are completely permeable to HRP. These variables must be considered in future studies of permeability in experimental brain tumors. Care must be exercised in extrapolating results about permeability from one brain tumor model to another.

Animals↗
PubMed1999

Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora.

The normal intestinal epithelium provides a barrier relatively impermeable to luminal constituents. However, patients with inflammatory bowel disease experience enhanced intestinal permeability that correlates with the degree of injury. IL-10 gene-deficient mice were studied to determine whether increased intestinal permeability occurs as a primary defect before the onset of mucosal inflammation or is secondary to mucosal injury. At 2 weeks of age, IL-10 gene-deficient mice show an increase in ileal and colonic permeability in the absence of any histological injury. This primary permeability defect is associated with increased mucosal secretion of interferon-gamma and tumor necrosis factor-alpha, and does not involve an increase in nitric oxide synthase activity. Colonic permeability remains elevated as inflammation progresses, while ileal permeability normalizes by 6 weeks of age. IL-10 gene-deficient mice raised under germ-free conditions have no inflammation, and demonstrate normal permeability and cytokine levels. This data suggests that the intestinal permeability defect in IL-10 gene-deficient mice occurs due to a dysregulated immune response to normal enteric microflora and, furthermore, this permeability defect exists prior to the development of mucosal inflammation.

Animals↗
PubMed2004

Exacerbation of intestinal permeability in rats after a two-hit injury: burn and Enterococcus faecalis infection.

OBJECTIVE: To determine alterations in intestinal epithelial permeability to solutes in burn injured rats with and without Enterococcus faecalis infection and the role of neutrophils in the intestinal permeability changes. DESIGN: Prospective sham-controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats were subjected to 30% total body surface burn (B group), E. faecalis infection (EF group) induced via intra-abdominal implantation of bacterial pellet, or combination of burn injury and E. faecalis infection (B+EF group). MEASUREMENTS AND MAIN RESULTS: In vivo measurements of intestinal permeability were carried out after intraluminal injection of H lactulose and C mannitol in the ileum of sham, B, EF, and B+EF groups of rats, 1 and 2 days after injury. Lactulose permeability was increased in the injured rat groups (B, EF, B+EF) on day 1 postinjury compared with sham. The combined injury group (B+EF) had the highest level of lactulose permeability. Although a significant change in lactulose permeability from day 1 to day 2 postinjury could not be demonstrated in the B and EF groups, lactulose permeability in the B+EF group on day 2 postinjury markedly decreased from day 1 but was still significantly higher than that in the sham group. Mannitol permeability was increased in all injured rat groups on day 1 postinjury; on day 2 it remained elevated post-B, decreased post-EF, and further increased after B+EF. Ex vivo measurements of lactulose movements across intestinal epithelial monolayers (IEC-18) were carried out in the presence of blood neutrophils from sham, B, EF, or B+EF rats. We also measured ex vivo transepithelial migration of neutrophils from sham, B, EF, or B+EF rat groups. Neither the transepithelial lactulose movement in the presence of neutrophils from, nor neutrophil migration in, the B or EF rats was significantly different from sham. However, a significant increase in transepithelial lactulose movement and neutrophil migration occurred in the B+EF group. Immunoblot analyses and in situ histochemical localizations of intestinal tight junction proteins, occludin and claudin-3, showed decreases in the distribution of occludin but not claudin-3 in the B, EF, and B+EF groups. CONCLUSIONS: Alterations in intestinal solute permeability and disruption of tight junction integrity after a two-hit injury with burn and E. faecalis infection, but not after individual injuries of burn or E. faecalis infection, are likely associated with heightened neutrophil flux across the intestinal epithelium.

Animals↗
PubMed2005

Gut permeability in neonates after a stage 1 Norwood procedure.

OBJECTIVE: Intestinal mucosal ischemia can occur during and after cardiac surgery. Severe decreases in mucosal perfusion may be a causative factor for postoperative mortality or complications such as necrotizing enterocolitis. Mesenteric perfusion is challenged preoperatively due to an imbalance between the systemic and pulmonary circulations and challenged intraoperatively due to hypothermic circulatory arrest. We have investigated gut permeability in seven patients undergoing stage 1 of the Norwood procedure, applying the dual sugar permeability test with L-rhamnose and lactulose. DESIGN: Seven patients with hypoplastic left heart syndrome: clinical presentation, gut permeability findings, and outcome. SETTING: A 10-bed mixed pediatric intensive care unit in a university hospital. PATIENTS: Seven patients admitted for postoperative care after cardiac surgery. INTERVENTIONS: Determination of gut permeability with the dual sugar permeability test using lactulose and rhamnose. Intestinal permeability was measured after induction of anesthesia and 12 and 24 hrs later. MEASUREMENTS AND MAIN RESULTS: : All patients had abnormal lactulose/rhamnose ratios. One patient, who had a lactulose/rhamnose ratio 12 hrs after surgery of 2.3 (46-times normal), developed necrotizing enterocolitis postoperatively and died 3 days after surgery. CONCLUSIONS: Gut permeability as assessed by the dual sugar permeability test is abnormal in patients with hypoplastic left heart syndrome before and after surgery. Lactulose/rhamnose ratios 46 times the normal value reflect a highly permeable small intestine. This may be a sign of a low output state and may help to identify patients at risk of developing necrotizing enterocolitis.

Cardiopulmonary Bypass↗
PubMed2006

Modulation of endothelial monolayer permeability induced by plasma obtained from lipopolysaccharide-stimulated whole blood.

The aim of this study was to elucidate the time course of the permeability response of endothelial monolayers after exposure to plasma obtained from lipopolysaccharide (LPS)-treated human whole blood; to investigate the role of apoptosis in monolayer permeability, and to inhibit the permeability increase, particularly after addition of the plasma stimulus. Human umbilical vein endothelial cells (HUVEC) were cultured on semiporous membranes and the permeability for albumin was measured after exposure, according to different schedules, to LPS-conditioned plasma. Apoptotic HUVEC were measured by both flow cytometry and ELISA. A variety of agents, including antibodies against cytokines, inhibitors of NF-kappaB, and a caspase inhibitor, were added to HUVEC, either prior to or after the stimulus. A maximum increase of the permeability was achieved after 4-6 h of exposure to LPS-conditioned plasma. This response was not accompanied by an increase in the number of apoptotic HUVEC. Administration of antibodies against both Tumour Necrosis Factor-alpha (TNF-alpha) and Interleukin-1beta (IL-1beta) to HUVEC within 1 h after stimulation significantly reduced the permeability increase. Similarly, pyrollidine di-thiocarbamate (PDTC), but not N-acetylcysteine, could prevent the permeability response, and was still effective when added within 2 h after LPS-conditioned plasma. The TNF-alpha/IL-1beta signal present in LPS-conditioned plasma appears to increase endothelial permeability through intracellular pathways that very likely involve the activation of NF-kappaB. Although poststimulatory inhibition of the permeability response proves to be possible with agents such as PDTC, the window of opportunity appears very small if placed in a clinical perspective.

Antibodies↗
PubMed1989

Effects of hydroxyethyl rutosides upon the permeability of single capillaries in the frog mesentery.

1. We have investigated the effects of a standardised mixture of hydroxyethyl rutosides (HR) upon the permeability of the walls of single capillaries and venules of the frog mesentery. 2. In each experiment a single vessel was perfused via a micropipette with frog Ringer solutions containing bovine serum albumin (10 mg ml-1) and Ficoll 70 (40 mg ml-1) first in the absence of HR and then with HR added to the perfusate. The permeability of the vessel walls was assessed during each perfusion by using a development of the Landis micro-occlusion technique to estimate their hydraulic permeability (Lp) and the effective osmotic pressure (sigma delta pi) exerted across them by the perfusate macromolecules. 3. Measurements were made both in vessels which appeared to be healthy and in vessels showing signs of stasis or inflammation before perfusion. 4. HR at concentrations of 1.0, 0.1 and 0.01 mg ml-1 reduced hydraulic permeability to approximately half of its value in the absence of HR. It increased sigma delta pi to macromolecules at concentrations of 10, 1.0, 0.1, 0.01 and 0.001 mg ml-1. The effects of HR upon permeability were not reversed within 10 min of perfusion with an HR-free solution. 5. Ultrastructural examination of a number of vessels in which initial high values of permeability were reduced to values within the normal range of permeabilities by HR, showed clear signs of damage to the endothelium, with large gaps between adjacent endothelial cells. 6. These observations suggest that HR does reduce microvascular permeability both in healthy vessels and vessels showing of inflammation. The reduction in permeability of inflamed vessels does not appear to be the result of closure of the gaps between adjacent endothelial cells.

Animals↗
PubMed1991

Effects of endothelin-1 on vascular permeability in the conscious rat: interactions with platelet-activating factor.

1. The objectives of the present experiments were to assess the effects of endothelin-1 on the macrovascular permeability in selected vascular beds, to study the involvement of platelet-activating factor (PAF) in vascular responses to endothelin-1 and to examine the vascular effects of combined administration of endothelin-1 and PAF in conscious rats. 2. Intravenous bolus injection of endothelin-1 (0.1-2 nmol kg-1) resulted in a dose-dependent biphasic change in mean arterial blood pressure (MABP) with initial transient hypotension followed by a prolonged pressor action. These changes were accompanied by a dose-dependent increase in haematocrit values. 3. Endothelin-1 (0.1 and 1 nmol kg-1) increased dose-dependently the vascular permeability of the trachea, upper and lower bronchi, stomach, duodenum, spleen and kidney (up to 240%) as measured by the extravasation of Evans blue dye. The permeability of pulmonary parenchyma, liver and pancreas was not affected significantly by endothelin-1 treatment. 4. Pretreatment of animals with the specific PAF receptor antagonist, WEB 2086 (1 mg kg-1, i.v.) or BN 52021 (10 mg kg-1, i.v.) reduced the endothelin-1 (1 nmol kg-1)-induced rise in haematocrit by about 50 and 30%, respectively. Both antagonists were highly effective at inhibiting protein extravasation in the stomach, duodenum and kidney. On the other hand, BN 52021, but not WEB 2086, significantly attenuated the effect of endothelin-1 on permeability in the lower bronchi and spleen. Neither WEB 2086 nor BN 52021 modified the changes in MABP evoked by endothelin-1.5. When low doses of endothelin-1 (0.1 nmolkg-')and PAF (0.19nmolkg-')were administered simultaneously, enhanced protein extravasation was detected in the upper and lower bronchi, whereas neither endothelin-1 nor PAF by themselves affected vascular permeability in these tissues. These changes occurred in the absence of significant changes in MABP.6. Combined administration of higher doses of endothelin-1 (1nmolkg-') and PAF (1.9nmolkg-') resulted in marked increases (up to 530%) in protein extravasation in the airways, pancreas, stomach and duodenum. The effect of endothelin-1 on permeability was not affected by PAF in the spleen, whereas it was completely inhibited by PAF in the kidney. Combined injection of endothelin-1 and PAF resulted in a slight, but significant increase in MABP.7. The present findings show that endothelin-1 is capable of increasing vascular permeability in selected vascular beds including the airways, gastrointestinal tract and kidney, and suggest that PAF may mediate, in part, its action on permeability, but not its hypotensive action. The present data also suggest that endothelin-1 and PAF can act in concert to increase vascular permeability in rat airways and gastrointestinal tract.

Animals↗
PubMed1995

Prostaglandins reduce hydrochloric acid-induced increase in duodenal mucosal permeability by a mechanism not related to stimulation of alkaline secretion.

The aim was to investigate whether prostaglandins affect HCl-induced mucosal permeability and to elucidate the role of mucosal bicarbonate secretion in protection. Proximal duodenum of anaesthetized rats were perfused with hydrochloric acid and the effects on luminal alkalinization, mucosal permeability and morphology examined in the absence and in the presence of prostaglandin E2 and/or indomethacin. Luminal alkalinization was determined by back titration of the perfusate and mucosal permeability assessed by measuring the clearance of 51Cr-labelled ethylenediaminetetraacetat ([51Cr]EDTA) from blood-to-intestinal lumen. Perfusion with 100 mM HCl for 5 min increased mucosal permeability sixfold and caused villus tip damage. Luminal administration of PGE2 at a concentration of 10(-6) M had no effect whereas 10(-4) M increased alkalinization by 100% but neither concentration affected the HCl-induced increase in mucosal permeability. PGE2 (10(-4) M), however, improved the ability of the duodenal mucosa to recover from the HCl-induced increase in mucosal permeability. Indomethacin (5 mg kg-1, i.v.) increased alkalinization, augmented HCl-induced mucosal permeability and aggravated mucosal injury. In animals pre-treated with PGE2 plus indomethacin, the HCl-induced increases in mucosal permeability were lower and injury less pronounced than in animals treated with indomethacin alone. No correlation was found between the rate of alkalinization and the HCl-induced increase in mucosal permeability. It is concluded that endogenous prostaglandins reduced the extent of 100 mM HCl-induced duodenal mucosal damage by a mechanism other than the stimulation of alkaline secretion.

Animals↗