Tumor necrosis factor alpha-induced pulmonary vascular endothelial injury
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Tumor necrosis factor alpha (TNF-alpha) mediates components of the acute-phase response, stimulates granulocyte metabolism, and induces endothelial cell surface changes. We studied whether human recombinant TNF-alpha (rTNF-alpha) could increase pulmonary edema formation and pulmonary vascular permeability. Rabbits preinfused with 125I-albumin were administered rTNF-alpha or saline. Animals were sacrificed, and lung wet/dry weight ratios as well as bronchoalveolar lavage fluid and plasma 125I activities were determined. rTNF-alpha increased lung wet/dry weight ratios by 151% (P less than 0.02) and bronchoalveolar lavage fluid/plasma 125I activity ratios by 376% (P less than 0.01) compared with values for saline controls. Electron microscopy of lung sections demonstrated endothelial injury, perivascular edema, and extravasation of an ultrastructural permeability tracer. To demonstrate that rTNF-alpha could directly increase pulmonary vascular endothelial permeability in vitro, we studied albumin transfer across cultured porcine pulmonary artery endothelial cell monolayers. rTNF-alpha induced time-dependent dose-response increments in transendothelial albumin flux in the absence of granulocyte effector cells. These observations suggest that rTNF-alpha can provoke acute pulmonary vascular endothelial injury in vivo as well as in vitro.Keywords:
Extravasation
Vascular permeability
Extravasation
Vascular permeability
Intravital microscopy
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Vascular hyperpermeability contributes to morbidity in inflammation. Current methodologies for in vivo assessment of permeability based on extravasation of Evans Blue (EB)-bound albumin are cumbersome and often lack sensitivity. We developed a novel infrared fluorescence (IRF) methodology for measurement of EB-albumin extravasation to quantify vascular permeability in murine models. Vascular permeability induced by endotoxaemia was examined for all solid organs, brain, skin and peritoneum by IRF and the traditional absorbance-based measurement of EB in tissue extracts. Organ IRF increased linearly with increasing concentrations of intravenous EB (2.5-25 mg/kg). Tissue IRF was more sensitive for EB accumulation compared to the absorbance-based method. Accordingly, differences in vascular permeability and organ EB accumulation between lipopolysaccharide-treated and saline-treated mice were often significant when analysed by IRF-based detection but not by absorbance-based detection. EB was detected in all 353 organs analysed with IRF but only in 67% (239/353) of organs analysed by absorbance-based methodology, demonstrating improved sensitivity of EB detection in organs with IRF. In contrast, EB in plasma after EB administration was readily measured by both methods with high correlation between the two methods (n=116, r2=0.86). Quantitation of organ-specific EB-IRF differences due to endotoxin was optimal when IRF was compared between mice matched for weight, gender, and age, and with appropriate corrections for organ weight and EB plasma concentrations. Notably, EB-IRF methodology leaves organs intact for subsequent histopathology. In summary, EB-IRF is a novel, highly sensitive, rapid, and convenient method for the relative quantification of EB in intact organs of treatment versus control mice.
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Vascular permeability
Absorbance
Serum Albumin
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To determine the role of neutrophil elastase in allergen-induced airway microvascular leakage, we assessed vascular permeability of guinea pig trachea by measuring the extravasation of Evans blue dye in the circulating blood. Inhalation of ovalbumin (OA) to guinea pigs sensitized with OA caused Evans blue extravasation, indicating an increased microvascular permeability. Pretreatment with ONO-5046 a specific inhibitor of neutrophil elastase, inhibited OA-induced vascular leakage in a dose-dependent manner. Tracheal instillation of human neutrophil elastase likewise increased microvascular permeability, and this effect was almost completely abolished by ONO-5046. Challenge with OA increased the number of neutrophils and neutrophil elastase activity in the bronchoalveolar lavage fluid, and these effects were inhibited by ONO-5046. These results suggest that neutrophil accumulation into the airway and the subsequent release of neutrophil elastase may play a role in the airway microvascular leakage produced by antigen challenge.
Evans Blue
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Vascular permeability
Neutrophil elastase
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The objective of the present study was to assess whether inhibition of nitric oxide (NO) production could modulate vascular permeability in the coronary circulation in conscious rats. Intravenous injection of N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME, 2 mg kg −1 ) resulted in a slowly developing hypertension and evoked twofold increases in vascular permeability in the left ventricle and right atrium as measured by the extravasation of Evans blue dye. Maintenance of mean arterial blood pressure at the level observed following l ‐NAME injection by infusion of noradrenaline (620–820 ng kg −1 min −1 ) did not induce significant protein extravasation in the coronary circulation. l ‐NAME treatment markedly enhanced (up to 490%) protein extravasation both in the left ventricle and right atrium in response to platelet‐activating factor (PAF, 1.9 nmol kg −1 , i.v.) and endothelin‐1 (1 nmol kg −1 , i.v.). Noradrenaline infusion potentiated (up to 69%) endothelin‐1‐induced protein extravasation. The permeability effect of PAF was only slightly enhanced by noradrenaline. The present findings indicate that inhibition of endogenous NO synthesis leads to an increase in protein extravasation and to potentiation of the permeability effects of PAF and endothelin‐1 in the coronary circulation. These results also suggest that NO may be an important regulator of vascular permeability under physiological and pathological conditions.
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Evans Blue
Vascular permeability
Coronary circulation
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The effect of bilateral adrenalectomy on the sensitivity of blood vessels in rat airways to mediators that increase vascular permeability was examined. An increase in vascular permeability was induced by intravenous platelet activating factor (PAF, 50, 100, 500, 1000 ng kg −1 ) and measured by quantifying the extravasation of Evans blue dye. PAF consistently increased the amount of Evans blue extravasation in the larynx, trachea, main bronchi and intrapulmonary airways in sham‐operated rats. The magnitude of this extravasation was significantly greater in the larynx ( P < 0.05), trachea ( P < 0.05) and main bronchi ( P < 0.05) of the adrenalectomized rats than it was in these tissues of the sham‐operated rats. When adrenalectomized rats were given subcutaneous dexamethasone (0.2 mg kg −1 4 h before PAF) the amount of plasma extravasation produced by PAF was decreased to the level of the sham‐operated rats. We conclude that adrenalectomy potentiates the increase in airway vascular permeability induced by PAF in rats and that this effect may be due to the depletion of endogenous corticosteroids.
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Evans Blue
Vascular permeability
Platelet-activating factor
Bilateral adrenalectomy
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We studied the effects of the potent inflammatory mediator, platelet-activating factor (PAF), on vascular permeability in airways (and other tissues) of guinea pigs by measuring extravasation of circulating Evans blue dye. PAF caused a dose-dependent increase in vascular permeability. At 1 ng/kg iv, PAF caused an increase in Evans blue extravasation of 220% (P less than 0.05) in the trachea, with the greatest effect at a dose of 100 ng/kg (858%; P less than 0.01). Histamine (150 micrograms/kg iv) caused a 320% increase over base line in the trachea and 200% in main bronchi; this effect was equivalent to that induced by 10 ng/kg PAF in the trachea and 1 ng/kg in main bronchi. The duration of effect of PAF was greatest in main bronchi (less than 10 min). Platelet depletion with a cytotoxic antibody, or the cyclooxygenase inhibitor, indomethacin, or the cyclooxygenase-lipoxygenase inhibitor, BW 7556, did not affect the vascular permeability response to PAF. The PAF-receptor antagonist, BN 52063, inhibited Evans blue extravasation in the airways in a dose-dependent manner, with complete inhibition at 5 mg/kg. Thus PAF-induced airway vascular leakage is mediated by specific receptors but not by products of arachidonic acid metabolism or by platelets. Increased airway microvascular leakage induced by PAF may lead to plasma extravasation and airway edema, factors that may contribute to the airway narrowing and hyperresponsiveness induced by PAF.
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Evans Blue
Platelet-activating factor
Vascular permeability
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Extravasation
Platelet-activating factor
Evans Blue
Vascular permeability
Parenchyma
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Abstract
Three methods for assessing the extravasation of serum albumin in tissues (skin) and intended to demonstrate increased vascular permeability (IVP) in (immunopathological) inflammation sites have been compared.
The radioassay (extravasated 131I-serum albumin counting) gave the values theoretically expected and was chosen as the reference technique. Two colorimetric techniques based on extravasation of Evans' blue bound in vivo to endogenous serum albumin were compared with it at cutaneous sites in which the vascular permeability had been increased by graded histamine reactions and delayed hypersensitivity reactions. The first technique makes use of a densitometer and has been found more precise than the second. A correlation curve was established between extravasated blue serum albumin (densitometric units) and extravasated radiolabelled serum albumin (c.p.m.). The second technique assesses the area of the blue spot, and the concentration of blue (by naked eye comparison with a carefully prepared and calibrated reference skin). It was found to be reliable and reasonably satisfactory, especially for studies including a great number of IVP sites.
Extravasation
Evans Blue
Vascular permeability
Serum Albumin
Densitometry
Densitometer
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Abstract Aim: The vascular protein permeability is dependent on the integrity of the vascular wall. The heart capillaries in male mice lacking β3 integrins have an immature phenotype. Previously, we have demonstrated a role for αvβ3 integrins in control of interstitial fluid pressure (Pif) and thereby in the fluid flux during inflammation. We wanted to explore a possible role for αvβ3 integrins in controlling capillary protein permeability during control situation and inflammation. Methods: We performed double‐tracer and microdialysis experiments on β3‐integrin‐deficient mice and wild type control mice. We also measured blood pressure and heart rate in the two mice strains. Results: We found reduced albumin extravasation (during 25 min) in the heart capillaries (0.053 ± 0.003 vs. 0.087 ± 0.009 mL g −1 dw, P < 0.05), and an increased cardiac mass/body weight (5.3 × 10 −3 ± 0.3 × 10 −3 vs. 3.8 × 10 −3 ± 0.1 × 10 −3 , P < 0.01) in the β3‐integrin‐deficient mice ( n = 6) compared with the controls ( n = 6). Heart rate and blood pressure were the same in mice with and without β3‐integrins. No difference in permeability was found in other tissues studied, or under local inflammation. Conclusion: These results show a function for the αvβ3 integrin in the regulation of protein permeability, selective for the heart capillaries.
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Interstitial space
Microdialysis
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Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis. Metastatic cells are thought to influence vascular permeability through secreted factors but the mechanisms are unclear. Here, the authors identify melanoma-secreted SPARC as a major regulator of cancer cell extravasation that modulates endothelial intercellular junctions.
Extravasation
Leukocyte extravasation
Vascular permeability
Matricellular protein
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