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PubMed1968

The ultrastructural basis of alveolar-capillary membrane permeability to peroxidase used as a tracer.

The permeability of the alveolar-capillary membrane to a small molecular weight protein, horseradish peroxidase (HRP), was investigated by means of ultrastructural cytochemistry. Mice were injected intravenously with HRP and sacrificed at varying intervals. Experiments with intranasally instilled HRP were also carried out. The tissue was fixed in formaldehyde-glutaraldehyde fixative. Frozen sections were cut, incubated in Graham and Karnovsky's medium for demonstrating HRP activity, postfixed in OsO4, and processed for electron microscopy. 90 sec after injection, HRP had passed through endothelial junctions into underlying basement membranes, but was stopped from entering the alveolar space by zonulae occludentes between epithelial cells. HRP was demonstrated in pinocytotic vesicles of both endothelial and epithelial cells, but the role of these vesicles in net protein transport appeared to be minimal. Intranasally instilled HRP was similarly prevented from permeating the underlying basement membrane by epithelial zonulae occludentes. Pulmonary endothelial intercellular clefts stained with uranyl acetate appeared to contain maculae occludentes rather than zonulae occludentes. HRP did not alter the ultrastructure of these junctions.

Animals↗
PubMed1976

Vascular permeability induced by pancreatic exudate formed during acute pancreatitis in dogs.

Acute pancreatitis was produced in five dogs by injecting bile into the pancreatic duct. The capillary permeability effects of the exudate formed within the peritoneal cavity were studied by injecting the exudate intradermally into puppies. The amount of radioactively labeled albumin escaping from the circulation and appearing at the intradermal injection site was used as a measure of capillary permeability. It was observed that the peritoneal exudate, especially that produced in the early stage of bile induced pancreatitis, contains one or more substances which result in an increased capillary permeability when injected intradermally into puppies.

Amylases↗
PubMed2005

Pulmonary and renal function following cardiopulmonary bypass is associated with systemic capillary leak.

OBJECTIVE: The purpose of this study was to compare perioperative capillary permeability during cardiac surgery with subsequent pulmonary and renal function. DESIGN: An observational prospective comparison of capillary permeability (microalbuminuria) during and after cardiopulmonary bypass (CPB), with postoperative pulmonary and renal function. SETTING: A university teaching hospital. PARTICIPANTS: Forty patients, mean (range) age 67.8 (50-85) years, undergoing elective first-time coronary artery bypass grafting (CABG). INTERVENTIONS: Urine albumin concentration (AC) and albumin creatinine ratio (ACR) were compared with PO2 /FIO2 ratio, mechanical ventilation (intermittent positive-pressure ventilation [IPPV]) duration, and renal function. MEASUREMENTS AND MAIN RESULTS: Median (range) AC and ACR increased from 8.3 (1.6-184.2) mg/L and 0.65 (0.1-18.8) mg/mmol preoperatively to 13.6 (1.6-267.2) mg/L and 4.80 (0.3-54.2) mg/mmol 10 minutes postbypass (p = 0.003 for ACR Wilcoxon rank test: not significant for AC). AC 2 hours postbypass was associated with mean PO2 /FIO2 ratio 0 to 2 hours postbypass and AC 4 hours postbypass was associated with mean PO2 /FIO2 ratio 0 to 2 and 2 to 12 hours postbypass (p < 0.05 Spearman). ACR 2 hours postbypass was associated with mean PO2 /FIO2 ratio 0 to 2 and 2 to 12 hours postbypass (p < 0.05 Spearman). AC 10 minutes and 2 hours postbypass and ACR 2 hours postbypass were associated with the duration of IPPV (p < 0.03). Day 1 serum creatinine was associated with pre- and 4 hours postbypass AC and ACR (p < 0.05). Day 2 serum creatinine was associated with 2 and 4 hours postbypass ACR (p < 0.05). CONCLUSIONS: The magnitude of increase in capillary permeability during CABG is associated with later pulmonary and renal function.

Aged↗
PubMed1986

Controversies in the fluid management of post-traumatic lung disease.

The appropriate intravenous therapy for injured patients is controversial. Use of colloid-containing solutions has been advocated in an attempt to maintain intravascular colloid osmotic pressure, minimize pulmonary oedema and draw fluid out of areas of contused lung. Studies of animals with lymph fistulas in the lung do not support such therapy and there is no difference between lung water volumes in animals resuscitated for 3 hours with colloid as opposed to crystalloid solutions after a standardized traumatic insult (colloid = 8.4 + 0.8 ml/kg; crystalloid = 7.5 + 0.6 ml/kg). Increased pulmonary capillary permeability makes such therapeutic attempts to 'dry out' the lungs even less effective. Studies in human patients of the rate of extravasation of labelled albumin from the pulmonary intravascular space indicate that increased permeability of pulmonary capillaries occurs early after injury and remains elevated in many severely injured patients. Low plasma colloid osmotic pressures do not correlate with increases in extravascular lung water. A shift to the use of vigorous crystalloid resuscitation of injured patients at our institution has resulted in decreases in both mortality rate (1976-1979, 35 per cent; 1979-1981, 28 per cent) and the rate of dialysis-dependent renal failure (1976-1979, 6 per cent; 1979-1981, 2 per cent). Current evidence supports the use of crystalloid solutions together with blood for resuscitation after injury.

Albumins↗
PubMed2003

A model of fluid flow in solid tumors.

Solid tumors consist of a porous interstitium and a neoplastic vasculature composed of a network of capillaries with highly permeable walls. Blood flows across the vasculature from the arterial entrance point to the venous exit point, and enters the tumor by convective and diffusive extravasation through the permeable capillary walls. In this paper, an integrated theoretical model of the flow through the tumor is developed. The flow through the interstitium is described by Darcy's law for an isotropic porous medium, the flow along the capillaries is described by Poiseuille's law, and the extravasation flux is described by Starling's law involving the pressure on either side of the capillaries. Given the arterial, the venous, and the ambient pressure, the problem is formulated in terms of a coupled system of integral and differential equations for the vascular and interstitial pressures. The overall hydrodynamics is described in terms of hydraulic conductivity coefficients for the arterial and venous flow rates whose functional form provides an explanation for the singular behavior of the vascular resistance observed in experiments. Numerical solutions are computed for an idealized case where the vasculature is modeled as a single tube, and charts of the hydraulic conductivities are presented for a broad range of tissue and capillary wall conductivities. The results in the physiological range of conditions are found to be in good agreement with laboratory observations. It is shown that the assumption of uniform interstitial pressure is not generally appropriate, and predictions of the extravasation rate based on it may carry a significant amount of error.

Arteries↗
PubMed1976

[Distribution of intravenously injected enzymes of heterologous, homologous and autologous origin. Distribution and transport of cell enzymes within the extracellular space. III (author's transl)].

The disappearance rates of intravenously injected enzymes of heterologous, homologous and autologous origin were determined in rats. Within four hours after administration, the activities show an exponential decline, that is either mono- or biphasic. The constant of the exponential function is a measure of the capillary permeability. In the case of biphasic disappearance this holds true only for the first slope, whereas the second one represents the elimination of active enzyme molecules from the extracellular space. If the decline in enzyme activity is monophasic the elimination of those enzymes from the interstitial space is limited by the permeability of the capillary membrane. Enzymes of homologous and autologous origin (extracts of liver or muscle) show a close correlation between their molecular weights and their rates of distribution within the extracellular compartment. For heterologous enzymes (crystallized) such a correlation could not be found. Possible causes for these differences in distribution are discussed. Heterologous and/or crystallized enzymes seem not to be suited for studies on the distribution of cell enzymes within the extracellular space. After enzymes are released from injured cells they undergo the processes of distribution, transport and elimination which are superimposed. The effects of the distribution and transport of enzymes on the results of clinical studies on enzyme elimination are discussed. It seems questionable at this point to assume that from the elimination rate of enzymes and their actual plasma activity one can account for the amount of enzymes originally released from injured cells.

Animals↗
PubMed2004

No effects of acute hyperglycaemia and hyperinsulinaemia on skin microcirculation and endothelial markers in Type II diabetes mellitus.

BACKGROUND: Increased microvascular permeability is a hallmark of microangiopathy in Type I diabetes mellitus and is associated with endothelial dysfunction and haemodynamic alterations. Type II diabetes mellitus is characterized by insulin resistance and hyperinsulinaemia. The purpose of this study was to determine whether acute hyperinsulinaemia, under both normoglycaemic and hyperglycaemic conditions, increases skin capillary permeability through its effect on skin haemodynamics, capillary recruitment or circulating markers of endothelial dysfunction in Type II diabetes. METHODS: Nine Type II diabetic patients without microalbuminuria, (pre-) proliferative retinopathy or clinical neuropathy underwent three glucose clamps of 210 min., in random order, on separate days. A "standard" clamp (insulin-infusion rate 30 mU kg(-1) h(-1), glucose-target 5.0 mmol/L) was compared with a hyperinsulinaemic (insulin-infusion rate 150 mU kg(-1) h(-1), glucose-target 5.0 mmol/L) and a hyperinsulinaemic, hyperglycaemic (insulin-infusion rate 150 mU kg(-1) h(-1), glucose-target 12.0 mmol/L) clamp. Skin capillary permeability and density were measured using large-window sodium fluorescein videodensitometry, and skin blood flow by laser Doppler flowmetry. Endothelial dysfunction was estimated from increases in soluble intercellular adhesion molecule-1 (sICAM-1) and von Willebrand factor antigen (vWF). RESULTS: No differences were found in skin capillary permeability, skin haemodynamics and capillary density at the end of the three glucose clamp periods. sICAM-1 and vWF did not increase as compared to the standard glucose clamp. sICAM-1 (r=-0.76, p<0.05) and vWF (r=-0.71, p<0.05) correlated negatively with insulin sensitivity, but not with skin microcirculatory parameters. CONCLUSIONS: Acute hyperinsulinaemia, both with and without concomitant hyperglycaemia, does not increase skin microvascular permeability, haemodynamics or parameters of endothelial dysfunction in Type II diabetic patients. Furthermore, these data suggest that the coexistence of hyperinsulinaemia and endothelial dysfunction in Type II diabetes does not indicate a causal relationship, but may rather indicate decreased insulin sensitivity as a common underlying cause.

Antigens↗
PubMed1993

Effect of leukocyte adhesion and microvascular permeability on capillary perfusion during ischemia-reperfusion injury in hamster cheek pouch.

The role of leukocyte sticking and permeability changes in the variation of perfused capillaries induced by ischemia reperfusion was studied in the hamster cheek pouch microcirculation. The drugs utilized were the antiperoxidative agents allopurinol, the calcium antagonists verapamil and diltiazem, and phenidone and adenosine, which inhibit leukotriene formation as well as leukocyte adhesion to the endothelium. The microvasculature was visualized by a fluorescence technique. Ischemia was induced by clamping the cheek pouch for 30 minutes followed by 30 minutes of reperfusion. The increase in permeability, the perfused capillary length and the number of adhering leukocytes to venular vessel wall were measured. Ischemia and reperfusion were associated with increased permeability, increased number of leukocytes sticking to the venular wall, and decreased number of functional capillaries. Microvascular injury evidenced by increased permeability was apparent in the first 5 min of ischemia. All the drugs decreased the number of leukocytes sticking to the venular wall; allopurinol, verapamil and adenosine reduced the increase in permeability, whereas phenidone and diltiazem were effective only during ischemia. In addition verapamil and adenosine preserved capillary blood flow during reperfusion. In conclusion, leukocyte sticking is correlated with increased microvascular permeability, but not with decreased perfusion of the capillary bed. These data suggest that leukocytes did not play a prominent role in the reduction of functional capillaries at the end of reperfusion.

Adenosine↗
PubMed1994

Antinociceptive and antipyretic effects of alkaloids extracted from the stem bark of Hunteria zeylanica.

Effects of crude alkaloids extracted from the stem bark of Hunteria zeylanica Gard. (H. zeylanica) on nociceptive responses, capillary permeability, yeast-induced hyperthermia, pentobarbital-induced sleep, and spontaneous motor activity were investigated. Oral administration of 50 mg/kg H. zeylanica alkaloid extract significantly decreased the number of writhings induced by intraperitoneal acetic acid. The extract at 100-200 mg/kg significantly increased nociceptive threshold of the inflamed but not the non-inflamed paw in the Randall-Selitto test. Moreover, in the formalin test, the extract (100 mg/kg) significantly decreased licking activity in the late phase without affecting the activity in the early phase. However, the extract did not produce antinociceptive effect in the hot plate test, while it inhibited increase of vascular permeability induced by acetic acid in the capillary permeability test. Moreover, the extract dose-dependently reduced yeast-induced hyperthermia in rats without affecting normothermia. It did not affect pentobarbital-induced sleep, but significantly increased locomotor activity at 100 mg/kg. These results suggest that H. zeylanica alkaloid extract possesses antinociceptive and antipyretic effects, and that the former effect may be mediated by its anti-inflammatory action.

Acetates↗
PubMed1986

Transcapillary exchange in the hindlimb and intestine of dogs with right heart failure.

The effects of chronic right ventricular volume overload, congestive heart failure (HF) on transcapillary exchange of lipid-insoluble solutes in the hindlimb and small intestine were studied in anesthetized dogs. Using the single injection indicator diffusion method, extractions (E), capillary clearances (C), and capillary permeability surface area products (PS) of urea, sucrose, and inulin were measured in the hindlimb and small intestine of 16 control and 14 HF dogs. Right HF was caused by surgically produced tricuspid insufficiency. The HF dogs exhibited increased central venous pressures, right ventricular end diastolic pressure, and heart rates as well as gross ascites and pleural effusion. The small intestine of the HF dogs demonstrated increased E, C and PS values for all three solutes, while no changes were seen in the hindlimb. These changes in the capillary bed of the small intestine could be due to an increase in capillary permeability, and/or capillary surface area.

Animals↗
PubMed1997

Interleukin-2 increases transcapillary diffusion of sodium fluorescein in human skin.

Immunotherapy with interleukin-2 (IL-2) has been limited by dose-dependent systemic toxicities secondary effects inducing a "vascular leak" syndrome. The purpose of our study was directly to observe and to quantitate changes in skin capillary permeability in response to microinjection of IL-2 by measuring transcapillary diffusion of sodium fluorescein. Twelve healthy volunteers were studied. IL-2 (2.5 microliters; 45,000 i.u.) was injected into the subepidermal skin layer of the distal tibial plateau by using a new microinjection technique. At the opposite leg, an equivalent amount of the solvent was injected to serve as the intraindividual control site. Three and 24 h after injection, Na-fluorescein was given intravenously, and transcapillary diffusion of the dye was simultaneously recorded with two different video microscopes. Perivascular fluorescent light intensities (FLI) corresponding to transcapillary diffusion of the dye were measured in arbitrary units (AU) by videodensitometry around the sites of microinjection during playback of the videotapes. Mean FLI values representing microvascular permeability 10 s after dye appearance were at 3 h, 1,504 +/- 592 AU for IL-2 and 983 +/- 652 AU for the solvent; and at 24 h, 2,450 +/- 447 AU for IL-2 and 658 +/- 329 AU for the solvent. At 3 and 24 h, the mean values after IL-2 application were significantly enhanced (p < 0.05-0.005) when compared with the mean values after injection of the solvent. The results document that IL-2, as compared with the solvent, significantly increases transcapillary diffusion of Na-fluorescein, reflecting capillary permeability in human skin. The increase in capillary permeability may explain the edema-promoting effect of IL-2 after systemic application.

Administration, Cutaneous↗
PubMed1975

Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion.

Ventriculocisternal perfusions with five isotopically labeled drugs were performed in the rhesus monkey and the resultant tissue diffusion concentration profiles in caudate nucleus were analyzed. The periventricular distribution space with respect to perfusate concentration was measured and expressed as microliters per 100 mg wet weight: hydroxyurea = 56; methotrexate = 27; thiotepa = 28; 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) = 64 and cytosine arabinoside greater than 170. The apparent diffusion constants in caudate nucleus were determined for hydroxyurea and methotrexate (2.0 and 1.2 X 10(-6) cm2/sec, respectively); capillary permeability expressed as an extracellular space-transcapillary exchange half-time was estimated to be greater than 2 hours for both compounds. The extracellular fluid-transcapillary half-time was measured for thiotepa and BCNU (1.0 and 0.8 minute, respectively). Cytosine arabinoside continued to be concentrated by periventricular caudate nucleus during the course of perfusion; perfusate clearance measurements suggest a low capillary permeability. The apparent parenchymal diffusion constant and the capillary permeability of a drug in brain are discussed and are considered useful parameters for predicting drug levels after intrathecal administration.

Agar↗
PubMed2006

Microalbuminuria, blood pressure load, and systemic vascular permeability in primary hypertension.

BACKGROUND: Microalbuminuria, a powerful predictor of cardiovascular events, is thought to reflect widespread subclinical vascular abnormalities. To explore the pathogenesis of increased urinary albumin excretion in primary hypertension we evaluated systemic capillary permeability and ambulatory blood pressure (BP) measurement in two groups of matched untreated patients with (n = 11) and without (n = 29) microalbuminuria. METHODS: Albuminuria was measured as the mean of albumin-to-creatinine ratio (ACR) in three nonconsecutive first morning urine samples. Systemic capillary permeability was evaluated by transcapillary escape rate of albumin (TERalb) (ie, the 1-h decline rate of intravenous (125)I-albumin). Twenty-four-hour ambulatory BP, renal hemodynamics, and hormones of the renin-angiotensin-aldosterone system (RAAS) were also assessed. RESULTS: Patients with microalbuminuria showed greater body mass index (BMI) (P < .04), higher 24-h systolic and diastolic BP levels (P = .02), and higher capillary permeability to albumin (P < .02) as compared to normoalbuminurics. Renal hemodynamics and RAAS hormones were similar in the two groups. Univariate analysis showed that urinary ACR was related to ambulatory pressure components (P < .02), TERalb (r = 0.31, P < .05), smoking habits (r = 0.36, P = .02), and left ventricular mass index (LVMI) (r = 0.57, P < .001) among the whole study group. Logistic regression analysis showed that each 1% increment in TERalb or 10 mm Hg increase in systolic BP entailed an almost three times higher risk of having microalbuminuria. CONCLUSIONS: Microalbuminuria is associated with greater systemic BP load and increased vascular permeability in patients with primary hypertension.

Adult↗
PubMed1995

Protein loss and capillary protein permeability in dependent regions upon quiet standing.

Seven healthy males were exposed to quiet standing (15 min) after supine rest. Alterations in the total mass of plasma proteins were analysed from changes in plasma volume (PV; determination of control PV and subsequently of induced per cent PV changes using Hb/Hct) and protein concentration as revealed in arterial blood collected after standing. This approach adopted the concept that valid data on overall circulatory haemoconcentrations prevailing on standing can only be reached when blood is sampled on resumption of the recumbent posture, whereas conventional sampling from the standing subject provides erroneous information. The PV reduction on standing averaged 649 +/- 65 mL (16.9 +/- 1.0%). There were very similar net decreases in plasma (serum) total protein (7.6 +/- 0.8 g) and albumin (7.8 +/- 0.9 g). These findings permitted the following main conclusions of physiological and methodological pertinence: (1) Quiet standing leads to a clear-cut net decrease in the plasma protein content predominantly confined to albumin, in all probability via convection secondary to PV loss by filtration in dependent regions. (2) It is suggested that the albumin loss reflects a quite high capillary macromolecular permeability in the dependent limbs on standing preferentially confined to skin/subcutaneous tissues. (3) The albumin loss implies that plasma concentration changes of neither albumin nor of total protein can be used to describe the PV loss on standing. However, concentration changes of the plasma globulin fraction as a whole, expressed by the difference (total protein-albumin), seem to reflect PV alterations approximately.

Adult↗