Changes In Capillary Permeability Research Articles

Would routine avoidance of veno-veno bypass be possible during liver transplantation?

CC Primary failure of the liver is associated with the secondary dysfunction of virtually all other organ systems, including the cardiovascular, pulmonary, renal, and central nervous systems. Furthermore, liver transplantation is a major surgical procedure with accompanying life-threatening hemorrhage, massive transfusion, and shifts in body fluids. Such patients suffer from additional insult caused by clamping of the great vessels, including the inferior vena cava (IVC) and portal vein (PV) during the anhepatic stage. As a result, additional circulatory insufficiency to organs including the kidney, and acidosis, hypoxia, intestinal edema, and changes in gut mucosal capillary permeability may occur. To reduce these non-physiologic insults resulting from the clamping of great vessels, veno-veno bypass (VVB) has been used during the anhepatic stage. This technique involves cannulating the inferior vena cava and the portal vein, and diverting their blood flow away from the liver and back to the right heart, usually via an axillary vein or a subclavian vein. By doing so, decompression of the portal circulation, and a reduction of congestion in the lower extremities and splanchnic circulation can be achieved. However, the use of VVB has its own adverse effects, such as accidental decannulation, circuit clots, embolic events, prolongation of operation time, vessel injury, and coagulopathy [1]. Massive pulmonary thromboembolism resulting in fatal right heart failure, and congestion of the transplant liver has been reported [2]. Several studies have reported no clear advantage for the routine use of VVB in liver transplantation surgery [3,4]. Furthermore, the piggyback technique, which just tangentially clamps the recipient’s suprarenal caval segment, is becoming widely used for liver transplantation surgery and allows the hemodynamic disturbances during anhepatic stage to be minimised [5]. Accordingly, the regularity of use of VVB appears to vary across institutions. Although some centers never use the technique at all, and all surgeries are performed by using a piggyback technique with no complete clamping of the IVC, many use VVB in selected cases; others use the technique on every case routinely, the exception being small

Grading of Severity of the Condition in Burn Patients by Serum Protein and Albumin/Globulin Studies

Capillary permeability increases after inflammation with consequent leak of fluid, electrolytes, and proteins. The albumin molecule size being smaller (69 kDa) than the globulin molecule (90-156 kDa) will leak relatively at an early stage of the disease (with moderate increase in capillary pore size) than globulin leading to albumin/globulin reversal. In cases with severe permeability changes with rapid progression to larger pore size with simultaneous leak of both albumin and globulin, albumin/globulin reversal will not occur. In this study estimation the serum protein and albumin/globulin (A/G) ratio at frequent intervals was done to grade the severity of the condition of burn patients by assessing the severity of capillary leak.A total of 61 admitted patients (from March 2002 to December 2004) based on the protein values were divided into 3 groups (group 1: 6-8 g/dL, group 2: 5.1-5.9 g/dL, group 3: < or =5.0 g/dL), and all the patients who showed change in their protein levels during the study were shifted to appropriate group and were classified as group shifters. The mean survival time and mortality of various groups were compared, and A/G ratio of all the expired cases was analyzed.Group 3 patients showed higher mortality (95%) as compared to that in other groups (group 1 and 2: 0% each and group shifters: 30.2%). Median survival time of group 3 was significantly low as compared to that of group 1 (P < 0.0026), group 2 (P < 0.0006), and group shifters (P < 0.0000). In group shifters the mean time (days) required for shifting from one group to other just before death or discharge in survivors was significantly higher than that in expired cases. Of 26 cases expired during the study, initial A/G ratio at the time of first assigning the group was not reversed in 22 cases (84.6%).The study concluded that the severity (indicated by lower serum protein values) and speed (judged by A/G ratio changes and median survival time analysis) of capillary permeability changes were associated with high mortality, and therefore, it is possible to grade the severity of the condition in burn patients.

The use of an endothelium-targeted cationic copolymer to enhance the barrier function of lung capillary endothelial monolayers

Acute changes in lung capillary permeability continue to complicate procedures such as cardiopulmonary bypass, solid organ transplant, and major vascular surgery and precipitate the more severe disease state Adult Respiratory Distress Syndrome (ARDS). To date there is no treatment targeted directly to the lung microvasculature. We hypothesized that biomimetic polymers could be used to enhance passive barrier function by reducing the porosity of the endothelial glycocalyx and attenuate mechanotransduction by restricting the motion of the glycoproteins implicated in signal transduction. To this end, cationic copolymers containing methacrylamidopropyl trimethylammonium chloride (P-TMA Cl) have been developed as an infusible therapy to target the lung capillary glycocalyx in order to mechanically enhance the capillary barrier and turn off pressure-induced mechanotransduction. Copolymers were tested for functional efficacy by measuring both albumin permeability ( P DA) and hydraulic conductivity ( L p) across cultured endothelial monolayers. P-TMA Cl significantly decreased P DA in normal and inflamed cells and attenuated pressure-induced increases in L p. Decreases in L p across endothelial monolayers in the presence of P-TMA Cl is evidence of a dampening of mechanotransduction-induced barrier dysfunction. We show the potential for biomimetic polymers targeted to lung endothelium as a viable therapy to enhance endothelial barrier function thereby attenuating a major component of vascular inflammation.

No effects of bosentan on microvasculature in patients with limited cutaneous systemic sclerosis

The endothelium-derived vasoconstrictor molecule endothelin-1 (ET-1) has been suggested to play a role in the pathogenesis of Raynaud’s phenomenon (RP) and systemic sclerosis (SSc). We studied the effect of bosentan on microvascular structure and function in patients with RP secondary to limited cutaneous SSc in a mechanistic pilot study. In this single center, open study, 15 patients with limited cutaneous SSc were treated with bosentan for 16 weeks with a follow-up period of 4 weeks. Changes in microvascular structure and function were studied with assessment of vasodilatory microvascular responses using laser Doppler fluxmetry combined with iontophoresis, capillary permeability using fluorescence videomicroscopy, nailfold capillary microscopy, and serological markers of endothelial activation. No significant changes were seen in vasodilator responses to acetylcholine and sodium nitroprusside following bosentan treatment. No effect was noted on capillary permeability during treatment. The number of nailfold capillaries remained unchanged. The endothelial activation marker vascular cell adhesion molecule did not change during treatment, but levels of thrombomodulin significantly decreased after 12 weeks of treatment. Bosentan did not induce significant changes in vasodilator responses, capillary permeability, and capillary density during treatment, so no evidence was obtained for structural improvement of microvascular structure and function in this short-time mechanistic pilot study in patients with lcSSc.

Juxtafoveolar Telangiectasis Associated with Crest Syndrome

Purpose: To report a case of CREST syndrome associated with juxtafoveolar telangiectasias (JT). Design: Case report. Methods: Observational case report. Results: A 64-year-old woman affected with CREST syndrome developed bilateral visual loss. Capillary dilatation and permeability changes in the outer retina were noticed during an angiographic study. Optical coherence tomography (OCT) showed thickening with loss of the foveal depression and inner lamellar cyst. The patient was diagnosed as stage 3, group 2A JT associated with CREST syndrome. Conclusions: Finding JT in association with CREST syndrome suggests a common pathophysiologic process.

Albúmina en el paciente crítico: ¿Mito o realidad terapéutica?

Under normal conditions, the plasmatic oncotic pressure is determined mainly by albumin. Numerous trials in critically ill patients have showed that hypoalbuminemia is associated to poor outcome. So, the administration of exogenous albumin is an attractive therapeutic strategy, widely spread in different clinical scenes. Nevertheless, its use has been questioned in the last period and up to date there is no clear evidence of the real effectiveness and/or utility. This article reviews the physiological and pathophysiological concepts that would justify the use of synthetic albumin. According to current literature, discussion about the rationality of its use in different pathological situations exists, trying to outline those clinical conditions that could or could not benefit with its administration. Certainly, clinical guidelines with recommendations about the benefits and indications of this therapy are required. Hypoalbuminemia in the critically ill patient is produced principally by redistribution, secondary to changes in capillary permeability: transcapillary leakage. The crucial interrelation between osmotic plasmatic pressure and albumin concentration in healthy individuals is lost in several critical conditions. Agreements on indications for use of albumin have not been achieved, since in different clinical context (resuscitation, sepsis, post-surgical, burns, nephrotic syndrome, ARDS) there are no significant advantages in morbidity and mortality of critically ill patients, compared to other cristalloids or synthetic colloids used. It is extremely important to develop clinical guidelines with recommendations on benefits and indications for the use of albumin in critically ill patients.

Response to Field

We read with interest the commentary (1) accompanying our article (2) in the October issue of the JCI. We appreciate Michael Field’s opinion that based on our data, the concept of secretory diarrhea must be revised to include the idea that net water secretion, or diarrhea, can occur in the absence of active ion secretion. However, we disagree with his conclusion that TNF must affect capillary permeability or smooth muscle contractility to generate increased interstitial pressure and a hydraulic driving force for water secretion. In contrast to Field’s suggestion, our study of 2 TNF superfamily members, TNF and LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry mediator on T cells), demonstrates that water secretion occurs as a consequence of epithelial Na+ malabsorption and increased epithelial paracellular permeability. This is supported by the observation that although TNF and LIGHT cause quantitatively similar paracellular permeability increases, only TNF causes diarrhea. The key difference that accounts for this is that only TNF activates PKCα, thereby inhibiting Na+/H+ exchanger isoform 3 (NHE3); TNF did not induce diarrhea when PKCα-mediated NHE3 inhibition was prevented by either pharmacological inhibitors or PKCα knockout. Could these approaches to PKCα inhibition have also prevented PKCα-dependent changes in capillary permeability or smooth muscle contractility? To test this we took advantage of the observation that LIGHT does not activate PKCα. LIGHT did cause diarrhea when PKC was activated pharmacologically, confirming that LIGHT was fully able to recapitulate TNF-like diarrhea when coupled with PKC activation. More importantly, direct NHE3 inhibition, either pharmacological or genetic, showed that this was the critical second component necessary for LIGHT to cause diarrhea. This was not due to inhibition of endothelial or smooth muscle NHE3, since neither tissue expresses NHE3. The unmistakable conclusion is that the necessary role of PKCα in TNF-induced diarrhea is to inhibit epithelial NHE3 and not to effect changes in capillary permeability or smooth muscle contractility. Why, then, is NHE3 so critical? Is it simply that Na+ absorption provides an osmotic driving force for water absorption? This alone is an inadequate explanation, as inhibition of absorption is not necessarily equivalent to induction of secretion. We propose that loss of NHE3-mediated Na+ absorption results in dissipation of the normal hyperosmolarity of the upper villus that drives water absorption (3). It then follows that increased paracellular permeability allows Na+ to leak from tissue to lumen; without NHE3, Na+ cannot be reabsorbed. Increased epithelial paracellular permeability may also allow water and other solutes to flow into the lumen, thereby compounding loss of the villous osmotic gradient that drives water absorption. In terms of absorption, the model gains further support from the observation that LIGHT-induced increases in permeability enhance water absorption (when NHE3 is active). Thus, this model fully explains the data without the need to invoke increased interstitial pressure to force water through paracellular or transcellular water channels. Is it therefore impossible for elevated interstitial pressure, secondary to increased capillary permeability or smooth muscle contraction, to contribute to TNF-induced diarrhea? It is not. However, if elevated venous or interstitial pressure were able to cause diarrhea by the mechanism proposed by Yablonski and Lifson (4) that is cited by Field (1), it is surprising that diarrhea is not a common clinical characteristic of patients with portal hypertension and that jejunal water and electrolyte transport are normal in these patients (5). We therefore conclude that TNF causes acute diarrhea via myosin light chain kinase–dependent increases in epithelial paracellular permeability coupled with PKCα-dependent NHE3 inhibition. Although intriguing as a hypothesis, no data support the role of increased interstitial pressure physically squeezing water into the lumen as proposed by Field. However, existing models of epithelial transport do provide an ample explanation for the observed synergy between increased epithelial paracellular permeability and Na+ malabsorption.

Protein permeability in lung injury: now in real time again?

the formation and the resolution of pulmonary edema is determined by several mechanisms, including lung vascular pressure, lung endothelial and epithelial permeability to protein, and the capacity of the alveolar epithelium to effectively remove alveolar edema fluid. Impaired alveolar fluid

Effect of Nitric Oxide Synthase Inhibition on Proteinuria in Glomerular Immune Injury

In glomerular immune injury, the inducible isoform of nitric oxide synthase (iNOS) becomes a major catalyst of NO production. Although iNOS-catalyzed NO production is sustained and can be cytotoxic, iNOS inhibition exacerbates the magnitude of proteinuria that accompanies immune injury. To investigate putative mechanisms of this effect, we assessed changes in glomerular permeability to albumin by using the following two approaches: (i) an in vivo rat model of glomerular immune injury induced by antibody against the glomerular basement membrane (GBM), in which urine albumin excretion was measured under conditions of iNOS inhibition, and (ii) an ex vivo model of isolated rat glomeruli, in which changes in glomerular capillary permeability to albumin were assessed under conditions of NOS inhibition. In rats with anti-GBM antibody-induced glomerular injury, there was an increase in urine albumin excretion. Treatment with two structurally dissimilar iNOS inhibitors at doses sufficient to decrease urine nitrate and/or nitrite exacerbated proteinuria. In these animals, urine excretion of the isoprostane 8-iso-PGF2alpha (marker of oxidative stress) was increased. In isolated glomeruli incubated with the NOS inhibitor L-NMMA, the permeability to albumin increased. This effect was reversed by the NO donor DETA NONOate and by the superoxide dismutase mimetic Tempol. We conclude that NOS-catalyzed NO production is an important mechanism in regulating glomerular permeability to protein. This mechanism involves control of the bioavailability of superoxide.

Dynamic Contrast-Enhanced MRI Quantification of Synovium Microcirculation in Experimental Arthritis

Our objective was to analyze MRI contrast-enhancement patterns in arthritic and nonarthritic knees and the relationship of those patterns with clinical, laboratory, and histologic synovium markers. Dynamic contrast-enhanced MRI was performed in nine arthritic and three nonarthritic knees of juvenile rabbits. A two-compartment pharmacokinetic model of signal intensity-time data was implemented to generate parametric maps of signal slope, maximal percentage of signal change, capillary permeability, leakage space volume, and time-to-peak. MRI values were compared with clinical, laboratory, and histologic markers for evaluation of synovial changes during the progression of arthritis. Parametric maps of capillary permeability and signal slope depicted significant differences between arthritic and nonarthritic knees. Arthritic knees showed increased capillary permeability (p = 0.006) and signal slope (p = 0.01) with time after onset of disease as opposed to nonarthritic knees (permeability, p = 0.65; slope, p = 0.56). Significant correlations were found between temporal changes in capillary permeability (p = 0.002), signal slope (p = 0.003), and serum concentrations of amyloid A. No relationship was noted between any MRI parameters and histologic scores. The discriminative power of MRI indexes varied according to the stage of arthritis: time-to-peak was most accurate for differentiation of presence versus absence of arthritis in early arthritis (day 1, p = 0.0002), and signal slope was most accurate in midterm arthritis (day 14, p = 0.001). In vivo capillary permeability and signal slope have distinctive dynamic MRI properties. The accuracy of MRI parameters for diagnostic evaluation of experimental arthritis differs according to the stage of disease.

Changes in plasma protein extravasation in rat skin during inflammatory challenges evaluated by microdialysis

Docetaxel and prostaglandin E1 (PGE1) increase transcapillary albumin extravasation and reduce interstitial fluid pressure in the skin. In this study the microdialysate concentration (Cm) of 125I-labeled human serum albumin (125I-HSA) and different-sized endogenous plasma proteins (EPP) was compared to evaluate changes in transcapillary extravasation of plasma proteins. 125I-HSA was also used to estimate changes in the specific activity of albumin. Extravasation of 125I-HSA and EPP from plasma to interstitium in the rat skin was compared during continuous administration of docetaxel and PGE1 by using microdialysis in anesthetized rats. Also, 20 ml of Ringer solution (RS) were injected intravenously during 10 min in a separate group. Two hollow plasmapheresis fibers (3 cm, cut off 3,000 kDa), one acting as control, were placed subcutaneously on the back skin and perfused with RS (5 microl/min, 140 min, collected every 10 min). The size of the different EPP was estimated to be 73, 65, 56, 47, and 39 A, separated by a size-exclusion high-performance liquid chromatography column and quantified by UV detection (280 nm). Docetaxel (0.5 mg/ml, n = 5) increased Cm of 125I-HSA and EPP of sizes 73, 65, 56, and 39 A significantly (P < 0.05) compared with control. PGE1 (20 microg/ml, n = 6) increased Cm of 125I-HSA significantly (P < 0.05) but none of the different-sized EPP was increased compared with control. Intravenous RS (20 ml, n = 6) increased Cm of 125I-HSA and increased all the different-sized EPP significantly (P < 0.05) compared with control. Although the microdialysis method is able to monitor qualitative changes in capillary permeability, a quantitative determination of the capillary reflection coefficient or permeability-surface area product was not possible, because steady state between plasma and dialysate was not achieved during the measurement period. The different pattern of extravasation of EPP and 125I-HSA after docetaxel, PGE1, and RS indicates increased interstitial transport rate and/or increased capillary permeability after docetaxel and RS, whereas PGE1 seems to increase transcapillary fluid flux without altering the permeability.

Cancer growth and spread are saltatory and phase-locked to the reproductive cycle through mediators of angiogenesis

The frequency of breast cancer metastatic spread is affected by the menstrual cycle phase of its resection. Breast cancer growth, post-resection spread, and cure frequency are each modulated by the estrous cycle in C(3)HeB/FeJ mice. Tumor metastases are 2- to 3-fold more frequent when the resection is done during diestrus as compared with estrus. Tumor angiogenesis is essential for both cancer growth and lethal metastatic cancer spread. The balance between vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) modulates new blood vessel formation and blood vessel permeability. Sex hormones modulate the expression of these key angiogenesis regulators in the endometrium and uterus. We, therefore, asked whether the estrous cycle modulates the density of CD31-positive vessels within the tumor, the permeability of tumor blood vessels, levels of VEGF and bFGF immunoreactive protein in normal breast and breast cancer, and whether expression of these genes are modulated by the estrous cycle stage in C(3)HeB/FeJ mice. We find that tumor blood vessel density and blood volume do not vary throughout the cycle; however, tumor capillary permeability is regulated by the estrous cycle being highest in diestrus, the cycle stage associated with the highest cancer growth rate and the highest frequency of post-resection cancer metastasis. VEGF protein levels in breast cancer are >100-fold higher than in normal breast. VEGF protein in this mammary tumor varies with the estrus cycle with highest levels in proestrus. In a non-breast tumor, methylcholantrenene A sarcoma, from CD(2)F(1) mice, tumor VEGF protein also varies with the estrus cycle with highest levels in proestrus and diestrus. VEGF gene expression in the mammary tumor does not change significantly across the cycle, but is modulated by the cycle in normal breast tissue. bFGF protein concentration is 6-fold higher in normal breast than in breast cancer. bFGF protein pattern in both tumor and breast are similar, opposite to VEGF, and affected by oophorectomy. bFGF message is modulated by the cycle in both breast cancer and normal breast. The changes in breast cancer capillary permeability, VEGF, and bFGF that occur during each fertility cycle, in breast tissue and breast cancer, putatively in response to cyclical changes in sex hormones, might contribute, at least in part, to both the modulation of cancer growth and post-resection breast cancer spread by the fertility cycle. These fertility cycle-induced effects on tumor biology also seem to extend to non-breast cancer biology.

Noninvasive evaluation of acute capillary permeability changes during high-volume ventilation in rats with and without hypercapnic acidosis*

To evaluate whether hypercapnic acidosis attenuates acute alterations of pulmonary capillary permeability due to high lung stretch in rats using a simple, noninvasive, scintigraphic method. Prospective, randomized, controlled animal study. University research laboratory. Male adult Wistar rats weighing 291 +/- 7.5 g. Three groups of rats were studied: controls ventilated with a low (6 mL/kg body weight) tidal volume and rats ventilated with a high (38 mL/kg body weight) tidal volume under normocapnic (Paco(2) = 35.2 +/- 1.65 mm Hg) or hypercapnic (Paco(2) = 102.5 +/- 5.63 mm Hg) conditions. Pulmonary capillary permeability alterations were assessed by monitoring the rate of (111)In-transferrin accumulation in lung tissue. Respiratory system pressure-volume curves were registered and analyzed. High tidal volume ventilation increased In-transferrin plasma to lung flux in such a way that I(111)In-transferrin behaved like a marker of water. The rate of initial (first 30 mins of high tidal volume ventilation) lung transferrin accumulation measured by scintigraphy (standardized lung/heart ratio) was steady, correlated with the percent decrease in respiratory system compliance (a marker of edema progression), and did not differ between normocapnic and hypercapnic groups (18.9 +/- 3.97 vs. 14.2 +/- 2.89%/hr, not significant). However, lung In-tranferrin accumulation rate was highly scattered due to variable interindividual mechanical properties of the respiratory system. This rate was correlated with initial values of volume of the upper inflection point of the pressure-volume curve (r = -.53, p < .001) and end-inspiratory pressure (r = .54, p < .001). Mechanical properties were similar in normocapnic and hypercapnic rats. There was no difference between In-transferrin accumulation rates in these rats when a stringent selection was made based on end-inspiratory pressure (28-32 cm H(2)O) or body weight (330-360 g). Hypercapnic acidosis does not influence in vivo the acute increase in pulmonary capillary permeability due to high-volume ventilation.

Biochemical and cytologic analysis of cystic contents in benign non‐parasitic symptomatic hepatic cysts before and after ethanol sclerotherapy

To examine the fluid of liver cysts by cytologic and biochemical analysis before and after ethanol sclerotherapy in order to explore the etiology of cystic fluid reproduction after sclerotherapy. The contents of 11 cysts in 11 patients were examined on the day of sclerotherapy, and 2-8 (mean 4.5) days later, and analysed for cytologic and biochemical parameters. Cytologic signs of acute or subacute inflammatory reaction were absent before and present in all cysts after sclerotherapy. Biochemical parameters reflecting the acute inflammatory reaction (CRP, orosomucoid and haptoglobine), changes in capillary permeability (protein, albumin), and the cystic epithelial function (bilirubin, alkaline phosphatase) were significantly elevated after sclerotherapy. The post-sclerotherapy fluid production is probably due to an inflammatory reaction. This may explain the success of performing sclerotherapy in one single session.

Ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome

Reduced total antioxidant capacity predicts ischaemia-reperfusion injury after femorodistal bypass.

Antioxidant defence systems are essential to protect the body from harmful free radicals released following ischaemia-reperfusion. The aim of this study was to examine the total antioxidant capacity (TAC) of patients with chronic critical leg ischaemia undergoing femorodistal bypass and to correlate this with lipid peroxidation, changes in capillary permeability and clinical outcome. Twenty-five patients, 15 men and ten women of median age 71 (range 62-79) years, and 15 matched controls were studied. Blood was taken before operation and after reperfusion, with assays performed for malondialdehyde (a product of lipid peroxidation) and total antioxidant capacity. Changes in capillary permeability were measured by changes in the urinary albumin:creatinine ratio (ACR) following reperfusion of the ischaemic leg and expressed as a percentage increase from the preoperative value. Clinical outcome in terms of the systemic inflammatory response syndrome (SIRS) was recorded. Vascular patients who developed clinical evidence of a systemic inflammatory reaction following revascularization had a significantly reduced TAC compared with the controls (490 versus 860 mumol/l; P < 0.01, Mann-Whitney U test). These patients also demonstrated an increase in lipid peroxidation (0.5 versus 0.25 mumol/l, P < 0.05) and vascular permeability, as measured by the percentage increase in ACR (365 versus 130 per cent, P < 0.01). Vascular patients with a lower TAC developed increased capillary permeability as a result of ischaemia-reperfusion, which progressed to SIRS. TAC may provide a test to identify 'at risk' patients. It may be possible to augment their defence with exogenous antioxidants.

Neutral and DEAE dextrans as tracers for assessing lung microvascular barrier permeability and integrity.

Steady-state lymph-to-plasma concentration ratios (L/Ps) of neutral dextrans, cationic DEAE dextrans, and endogenous proteins were determined under normal and increased permeability conditions in six unanesthetized yearling sheep prepared with chronic lung lymph fistulas. Fluorescent dextrans with radii ranging from 1 to 30 nm were intravenously infused, and after 24 h, perilla ketone (PK) was given to alter permeability while the dextran infusion was maintained. Plasma and lymph samples were collected before and after PK administration and analyzed for dextran and protein concentrations after high-performance liquid chromatography size separation. Under both baseline and increased permeability conditions, DEAE dextrans had higher L/Ps than neutral dextrans of similar size but lower L/Ps than proteins of similar size. Comparison of L/Ps before and after PK revealed that the percentage change in permeability for neutral and DEAE dextrans was significantly larger than that for proteins. These results suggest that 1) the pulmonary microvascular barrier behaves as a net negative barrier, 2) some transport mechanisms for proteins and dextrans are different, and 3) neutral and cationic dextrans are more sensitive markers than proteins of the same size for assessing changes in pulmonary capillary permeability.

Assessing Perfusion and Capillary Permeability Changes Induced by a VEGF Inhibitor in Human Tumor Xenografts using Macromolecular MR Imaging Contrast Media

Angiogenesis, the formation of new blood vessels, is essential for tumor growth. Inhibition of angiogenesis represents a novel strategy for the treatment of cancer (1). Vascular Endothelial Growth Factor (VEGFs) is a key angiogenic factor which stimulates endothelial cell proliferation and migration. VEGF may also contribute to disease progression through a profound permeabilizing effect on tumor vasculature. As such, inhibition of VEGF signal-transduction represents a good target for therapeutic intervention. The purpose of this study was to quantify perfusion and capillary permeability changes induced by the VEGF receptor tyrosine kinase inhibitor, ZD4190, using a macromolecular MRI contrast media, P 792.

Albuminuria in hypertension is linked to altered lysosomal activity and TGF-beta1 expression.

Increased intraglomerular pressure is considered a major factor for increased albumin excretion in hypertension. However, other factors should also be considered because recent studies in both humans and rats have demonstrated that proteins undergoing filtration and renal passage are extensively modified by renal cell lysosomal processing; >95% of albumin is degraded to peptides that are not detected by routine immunochemical assays. Changes in postglomerular lysosomal processing may therefore be responsible for the increased intact albumin excreted in hypertension-related kidney disease. We hypothesize that transforming growth factor-beta, which is known to decrease lysosomal activity, may be upregulated in hypertension and may play a role in increased intact albumin excretion. The aims of this study were to determine the effect that hypertension has on (1) renal cell lysosomal processing of albumin and dextran sulfate, (2) glomerular permeability, and (3) renal transforming growth factor-beta(1) expression. Spontaneously hypertensive rats and Wistar-Kyoto rats were used at 8, 16, and 24 weeks. We demonstrate that albuminuria in hypertension is linked to an inhibition of lysosomal processing as determined by (1) size exclusion chromatography analysis of urinary [(14)C]albumin structural integrity and (2) ion exchange analysis of urinary [(3)H]dextran sulfate. This inhibition gives rise to an increased proportion of radioimmunoassay detectable (intact) albumin and intact dextran sulfate independent of changes in glomerular capillary wall permeability as determined by the fractional clearance of [(3)H]Ficolls of various radii. These changes may be correlated with increased renal transforming growth factor-beta(1) expression.

Persistent multiple organ microcirculatory disorders in severe acute pancreatitis: experimental findings and clinical implications.

This study characterizes microcirculatory changes (capillary blood flow, capillary permeability, and leukocyte rolling) in the pancreas, colon, liver, and lungs at different stages of severe acute pancreatitis (AP) in a well-established rat model using intravital microscopy and computerized image analysis. The results demonstrate that microcirculatory disorders in severe AP are not confined to the pancreas but can also be found in the colon, liver, and lungs; that they extend beyond the early stage of AP and persist for 48 hr (and longer); and that they not only affect capillary blood flow but also involve prolonged changes of capillary permeability and leukocyte endothelial interaction. These findings may explain previous observations that therapeutic strategies aimed at enhancing microcirculation improve outcome in AP even if therapy is delayed and pancreatic necrosis can no longer be influenced. Since these systemic microcirculatory disturbances may contribute to AP-associated multiple organ dysfunction syndrome, further studies are warranted to evaluate whether improvement of microcirculation stabilizes organ function in AP and how long this may be effective after disease onset.