High Vascular Permeability Research Articles

Morphologic and histochemical study of blood capillaries in boar testes: effects of abdominal cryptorchidism.

Few data exist about the features of testicular microvasculature under normal and pathologic conditions. The morphology and lectin affinity of testicular capillaries were examined in healthy boars and in unilateral and bilateral abdominal cryptorchid boars. The capillaries of scrotal testes contained a) the endothelial layer formed by two cells, b) the basal lamina constituted by collagen fibers and glycoconjugates with fucosyl, galactosyl, glucosyl, and neuraminic acid residues, and c) the pericyte layer formed by a single cell. These components participated in substrate exchange between blood and testicular tissue. The abdominal testes showed increased numbers of capillaries, which could exhibit a mature appearance, but also angiogenic or degenerative patterns. Angiogenesis was manifested in interstitial capillaries and was characterized by a) proliferation of endothelial cells, b) decreased thickness and decreased content of collagen fibers and glycoconjugates in the basal lamina, and c) lack of pericytes. Degenerative capillaries lay in association with seminiferous tubules and showed a) pyknotic endothelial cells; b) thickening, collagenization, and altered glycoconjugate content in the basal lamina; and c) increased development of pericytes. The angiogenesis of interstitial capillaries resulted in high vascular permeability, and the degeneration of intertubular capillaries led to defective substrate exchange between blood and seminiferous tubules. Unilateral abdominal cryptorchidism did not alter the morphology and function of capillaries in the scrotal testis. Unilateral and bilateral abdominal cryptorchidism resulted in increased numbers and abnormal morphology and function of capillaries in abdominal testes. The proliferation of interstitial capillaries correlated with the immaturity of Leydig cells, and the degeneration of intertubular capillaries correlated with the thickening of the lamina propria.

Water Channel (Aquaporin 1) Expression and Distribution in Mammary Carcinomas and Glioblastomas

The aquaporins represent a family of transmembrane water channel proteins that are widely distributed in various tissues throughout the body and play a major role in transcellular and transepithelial water movement. Most tumors have been shown to exhibit high vascular permeability and high interstitial fluid pressure, but the transport pathways for water within tumors remain unknown. In this study, we examined the distribution of the aquaporin 1 (AQP1) water channel protein in several types of transplanted tumor. Two mammary carcinomas, MCaIV and R3230AC, and three glioblastomas, HGL21, U87, and F98, were implanted in rats and mice. Two sites of implantation in rodents were chosen: a cranial window (CW) region and a subcutaneous (SC) region. Tissues were studied using immunoblot analysis and immunofluorescence staining. In the mammary carcinomas, AQP1 was localized in vascular structures; no differences between CW and SC regions were observed. Among the three glioblastomas, HGL21 and U87 exhibited similar AQP1 localization in vascular structures, whereas the center of F98 did not show vascular staining. Cell membranes of normal epithelial cells did not show AQP1 expression, while membranes of most tumor cells exhibited significant AQP1 expression. Interestingly, however, HGL21 and F98 in the CW locations showed no AQP1 expression on tumor cell membranes. These results show that the AQP1 water channel is heterogeneously expressed in tumor cells and their vasculature, and that the level of expression is determined not only by the specific cellular origin of the tumor, but also by the location of the tumor in the host animal.

Isoproterenol attenuates high vascular pressure-induced permeability increases in isolated rat lungs.

To separate the contributions of cellular and basement membrane components of the alveolar capillary barrier to the increased microvascular permeability induced by high pulmonary venous pressures (Ppv), we subjected isolated rat lungs to increases in Ppv, which increased capillary filtration coefficient (Kfc) without significant hemorrhage (31 cmH2O) and with obvious extravasation of red blood cells (43 cmH2O). Isoproterenol (20 microM) was infused in one group (Iso) to identify a reversible cellular component of injury, and residual blood volumes were measured to assess extravasation of red blood cells through ruptured basement membranes. In untreated lungs (High Ppv group), Kfc increased 6.2 +/- 1.3 and 38.3 +/- 15.2 times baseline during the 31 and 43 cmH2O Ppv states. In Iso lungs, Kfc was 36.2% (P < 0.05) and 64.3% of that in the High Ppv group at these Ppv states. Residual blood volumes calculated from tissue hemoglobin contents were significantly increased by 53-66% in the high Ppv groups, compared with low vascular pressure controls, but there was no significant difference between High Ppv and Iso groups. Thus isoproterenol significantly attenuated vascular pressure-induced Kfc increases at moderate Ppv, possibly because of an endothelial effect, but it did not affect red cell extravasation at higher vascular pressures.

1 alpha,25-Dihydroxyvitamin D3 decreases scalding- and platelet-activating factor-induced high vascular permeability and tissue oedema.

We have previously demonstrated that 1,25-dihydroxyvitamin D3 decreases endotoxin-induced mortalities of rat and mouse from 80% and 70% to 14% and 10% (unpublished results). In the present study, pretreatment of 1,25-dihydroxyvitamin D3 decreased pad oedema and pulmonary vascular permeability induced by scalding and platelet-activating factor. 1,25-Dihydroxyvitamin D3 in a dose of 4 x 10(-9) mol/kg decreased pulmonary extravascular Evans blue concentration increased by platelet-activating factor from 6.32 +/- 0.63 ng/g to 2.57 +/- 0.28 ng/g (P < 0.01), and lung water/dry lung weight from 3.79 +/- 0.57 to 1.51 +/- 0.13 (P < 0.01). 1,25-Dihydroxyvitamin D3 of 4 x 10(-11) moles/kg and calcipotriol (a vitamin D analogue which has limited hypercalcaemic effect) of 4 x 10(-9) moles/kg had similar effects. Karyocyte counting of bronchoalveolar lavage fluid and the reduction of mean arterial pressure were also reduced to some extent. These results suggest that 1,25-dihydroxyvitamin D3 may be a new and effective drug to reduce vascular permeability and ameliorate oedema.

Suppression by isoproterenol of endothelial cell morphology and barrier function changes induced by platelet-activating factor.

Using a model to study vascular permeability on hydrostatically perfused bovine pulmonary artery endothelial cell (EC) monolayers and software to analyze cell morphological parameters automatically in a computer image workstation, we studied the effects of isoproterenol (IPN) on platelet-activating factor (PAF)-induced changes in EC monolayer permeability and cell morphological parameters. Albumin has fortifying effects on endothelial barrier function. As albumin concentration in the perfusate increased (0, 1, 5, 10, 20 mg/ml), EC monolayer hydraulic conductivity (Lp) decreased gradually while Lp of the filter membranes did not change. After treatment of the EC monolayer with PAF 10(-8) mol/liter for 30 min, transmonolayer fluid flow, protein clearance rate, and Lp value increased noticeably. At the same time, cell area decreased and intercellular distance and percentage of intercellular space area in total cell monolayer increased. Pretreatment with 10(-4) mol/liter IPN blocked PAF-induced EC permeability and morphological changes, suggesting that EC contraction and intercellular gap formation are important mechanisms for PAF-induced high vascular permeability. IPN inhibits the effects of PAF via stabilization of EC morphology, protection of intercellular junction, and blockade of intercellular gap formation.

Lymph Flow from Murine Footpad Tumors before and after Sublethal Hyperthermia

The effect of local hyperthermia (43.5 degrees C for 1 h) on lymph flow from B16-F10 tumor-bearing foot pads of C57BL/6 mice was measured by monitoring the clearance of 99mTc-labeled human serum albumin. The foot was represented by a single-compartment model enabling a quantitative computation of lymphatic flow from the tumor to regional lymph nodes. Lymphatic flow from untreated tumors was 0.0059 +/- 0.0011 ml/min cm3 compared to 0.0118 +/- 0.0027 ml/min cm3 lymphatic flow from tumors immediately following heating. Morphological alterations in tumor blood vessels result in their high vascular permeability. The increase in lymphatic clearance from tumors after sublethal hyperthermia is compatible with the increase in interstitial fluid formation in tumors based on Starling's Law.

A dual-isotope method for studying protein kinetics in pleural effusions in humans.

A method is described for studying protein kinetics in pleural effusions in humans. In 15 patients with pleural effusions from a variety of causes, protein inflow was monitored by measuring the rate of appearance in the effusion of the plasma protein transferrin, radiolabelled in vivo by intravenous injection of 113InmCl3. Protein outflow was measured from the rate of appearance in the blood of intrapleurally administered 125I-albumin. Compartmental analysis has been used to determine rate constants k(in) and kout for the movement of labelled proteins into and out of the effusion, respectively. The mean value of k(in) for 15 patients was 9.4 x 10(-4) h-1 (range 2.2-21.4). The mean value of kout in the same patients was 28 x 10(-4) h-1 (range 6-68). Using appropriate assumptions where necessary, the absolute transfer rates of albumin and transferrin were also estimated. For albumin, the mean rate of outflow was 66 mg h-1 (range 27-158), compared to mean estimated inflow of 133 mg h-1 (range 36-381). Protein inflow was highest in a case of metastatic ovarian carcinoma with pleural and peritoneal seedlings, indicating high vascular permeability. Protein outflow was very low in a case of mesothelioma, suggesting severely impaired lymphatic drainage. The technique may prove to be a useful tool for studying mechanisms resulting in the formation of malignant and nonmalignant pleural effusions, and may also be useful for studying the effects of putative therapeutic intervention.

Rectal absorption and distribution of Diflucortolone valerate and Lidocaine in hemorrhoid model rats.

Intrarectal application of drugs has been used as an effective administration route, howsver, the absorption and distribution of drugs may be changed in pathological state of the rectum, especially in the case of hemorrhoid disease. Rectal absorption and distribution of 3H-diflucortolone valerate (3H-DFV), which is an anti-inflammatory steroid, and 14C-lidocaine (14C-LDC) in hemmorrhoid model rats were compared with that in normal rats. The hemmorrhoid model rats, were prepared by means of application of croton oil into rectum of rats, showed high vascular permeability and edema. 3H-DFV and 14C-LDC were applied into the rectum as a suppository of combination of both drugs at the dose of 0.01mg/kg of 3H-DFV and 2mg/kg of 14C-LDC, and the anus was sealed by glue for 3h. Rectal absorption of 3H -DFV was slow and low, while that of 14C-LDC was faster than 3H-DFV. The profile and pharmacokinetic parameters (Cmax, Tmax and AUC) of blood kinetics of both radioactivities in the hemmorrhoid model rats were not different statistically from that observed in intact rats. These results indicate that the kinetics of rectal absorption of both drugs can't be changed by hemorrhoid disease. The radioactivity in the rectum, target tissue of anti-hemorrhoid drug, showed 100 folds higher value of that in the blood, and no difference in the radioactivities in the rectum was observed between intact and hemorroid rats. The autoradiogram revealed the uniform distribution of the radioactivities in the hemorrhoid rectum. These results indicate that the rectal application is more effective therapy than the systemic one, and the kinetics after rectal application shows no diffe rence between intact and hemorrhoid model rats.

Participation of serotonergic mechanisms in the pathophysiology of experimental neoplastic spinal cord compression

We evaluated the role of serotonin (5-HT) in neoplastic cord compression in paraplegic rats harboring a thoracolumbar epidural tumor. We measured serotonin and its major metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), in the C-1 to C-7, T-1 to T-6, T-7 to T-12, and T-13 to L-3 spinal segments of tumor-free and tumor-bearing rats. In normal controls, a consistent rostral-to-caudal gradient for 5-HT and 5-HIAA was evident, but the 5-HIAA/5-HT ratio remained constant. In paralyzed rats, 5-HT levels were unchanged, but the 5-HIAA/5-HT ratio was elevated, especially in the compressed segments. Treatment with either dexamethasone or indomethacin delayed onset of paraplegia but had no effect on 5-HT metabolism. Blocking 5-HT receptors by cyproheptadine, evaluated 30 hours after onset of paralysis and treatment, resulted in a reduction in the high water content, vascular permeability, and prostaglandin E2 synthesis in the compressed cord. Early administration of cyproheptadine effectively delayed the onset of paraplegia. These data indicate that receptor-activated serotonergic mechanisms participate in the disruption of the blood-spinal cord barrier and that these effects can be manipulated pharmacologically.

Uptake of 63Ni 2+ in the central and peripheral nervous system of mice after oral administration: Effects of treatments with halogenated 8-hydroxyquinolines

Oral administration of 63Ni 2+ to mice resulted in higher levels of the metal in the sciatic nerves, the trigeminal ganglia, spinal nerve roots and the spinal cord than in the cerebellum and the frontal cortex. In the sciatic nerves, the trigeminal ganglia and the spinal nerve roots a high vascular permeability may explain the preferential uptake of the 63Ni 2+. The higher accumulation of the 63Ni 2+ in the spinal cord than in the examined structures of the brain may be related to a diffusion from the cerebrospinal fluid. Administrations of halogenated 8-hydroxyquinolines [5,7-diiodo-8-hydroxy-quinoline (diI-HQ), 5,7-dibromo-8-hydroxyquinoline (diBr-HQ), 5,7-dichloro-8-hydroxyquinoline (diCl-HQ) or 5-chloro-7-iodo-8-hydroxyquinoline (Cl-I-HQ)] together with the 63Ni 2+ resulted in increased levels of the metal both in neural and extraneural tissues in comparison with mice given the 63Ni 2+ alone. In most instances the tissue-levels of 63Ni 2+ were 2–4 times higher in the animals treated with the halogenated 8-hydroxyquinolines than in the controls. Determinations of chloroform/water partition coefficients showed that lipophilic chelates are formed between each of these compounds and the nickel. Our results are probably explained by a facilitated passage of the complexed metal over the walls of the stomach and the intestine. The halogenated 8-hydroxyquinolines are linked with the SMON-syndrome, a disease which occured primarily in Japan. The possibility that this syndrome may be causally connected with a concomitant intake of these drugs and metals is discussed.

Quantitative morphology of human glioblastoma multiforme microvessels: structural basis of blood-brain barrier defect.

Neoplastic invasion of the brain parenchyma results in a disruption of the ultrastructure of the blood vessel walls such that serum proteins extravasate into the surrounding tissue, resulting in cerebral edema. The structural changes involved are not well understood, since the pores through which serum constituents pass (permeability routes) in normal barrier vessels and in tumor vessels where the barrier is compromised, have not been extensively explored. In this study we investigate the ultrastructure of human brain microvessels in biopsied samples of control brain tissue and five glioblastoma multiforme tumors. Electron micrographs of a total of 78 vessels were analysed with computer assisted morphometry for ultrastructural evidence of permeability routes. Fenestrations in the endothelium were not seen. Pinocytotic vesicle number and arrangement did not differ significantly from that seen in control brain vessels. Interendothelial junctions with enlarged distensions (which may represent sections through transendothelial channels) were seen in some vessels from most tumors but not in control barrier vessels. In addition, large gaps in the endothelial layer were seen in less than two percent of tumor vessels. In conclusion, glioblastoma multiforme vessels in this study show subtle alterations in vessel morphology from that seen in controls. We suggest that the high vascular permeability and resultant brain edema seen in glioblastoma multiforme tumors is likely due to the presence of channels through interendothelial junctions, and rare but large breaks in the endothelial wall.

Alterations in the peritoneal transport of water and solutes during peritonitis in continuous ambulatory peritoneal dialysis patients.

The in situ intraperitoneal volume and the mass transfer area coefficients (MTC) of urea, lactate, creatinine, glucose, kanamycin, inulin, beta 2-microglobulin, albumin and IgG were studied in eight continuous ambulatory peritoneal dialysis (CAPD) patients. All patients were studied during a 4-h dialysis dwell, first during peritonitis and subsequently after recovery from the infection. The maximal intraperitoneal volume was reached at 68 min during peritonitis and at 150 min in the study after recovery (P less than 0.01), suggesting increased water transport during the infection. For all investigated solutes MTCs were higher in the presence of peritonitis than after recovery. This increase was most marked for the proteins (greater than 100%). The power curve relationships between MTCs and molecular weight indicated that peritoneal transport of the low- and middle-molecular weight solutes was determined by free diffusion and that the infection-induced rise was due to an increase in effective surface area. For protein transport restricted diffusion was found. The increase of this transport during peritonitis was probably caused by both a larger effective surface area and a higher vascular permeability.

Collagen concentration and mast cell in perinatal murine uterus.

Edema was found in the uterine tissue on the day of parturition. The number of mast cells was increased significantly on this day, indicating that the time of appearance of the edema is identical to the time of a significant increase in the number of mast cells. These results suggest that mast cells induce the high vascular permeability that permits passage of collagenase-activating proteases to the uterine tissue from the serum.

THE EFFECT OF DOXORUBICIN ON SLOW AND FAST COMPONENTS OF THE AXONAL TRANSPORT SYSTEM IN RATS

The study was designed to investigate the changes in axonal transport that result from disturbances in protein synthesis. Doxorubicin, an antineoplastic drug which interferes with the function of DNA, has a selective effect on peripheral sensory nerves because of the high vascular permeability in the dorsal root ganglia. After the intravenous administration of a moderate dose (4 mg/kg) to male Wistar rats, the transport of slow component a (SCa) was found to be retarded, transport velocity being decreased by 17% (0.85 +/- 0.06 mm/day vs 1.03 +/- 0.06 mm/day in controls). The transport kinetics of the fast anterograde and retrograde components (aFC and rFC) were unchanged after the administration of a dose of 6 mg/kg, although the relative amount of aFC was decreased by 27% (3.2 +/- 0.9% vs 4.4 +/- 1.1% in controls). It is suggested that the neuronopathy induced by doxorubicin is mediated by changes in axonal transport.

Studies on the ?vascular labeling? phenomenon in the iris and the ciliary body of the rat after intravenous injection of colloidal carbon

The occurrence of carbon deposits after intravenous injection of colloidal carbon (vascular labeling phenomenon) in the iris and the ciliary body of the rat eye was studied by vital microscopy, unstained perfused mount preparations, and by electron microscopy. Generally in the untouched eye the vascular labeling phenomenon is either absent or appears only in the form of finest granular deposits in some capillaries and venules of the iris and the ciliary body. A decrease of intraocular pressure by paracentesis causes a certain blackening phenomenon, which prefers the capillaries and the venules of the iris and the capillaries in the ciliary processes. This effect is intensified by a further decrease of the intraocular pressure to -30 mm Hg. Predominantly the deposits are found stronger in the ciliary region than in the iris. Increase of the intraocular pressure of up to 30 mm Hg diminishes the blackening phenomenon. After administration of the vasodilator bencyclane into the anterior chamber the vascular labeling phenomenon shows a clear graduation of carbon affinity depending upon the concentration of the drug: The capillaries and venules are exclusively blackened at low concentrations, additionally the collecting venules and arterioles are influenced at medium and high doses. By electron microscopy an intraluminal as well as an intramural (subendothelial) deposition of carbon, partly accompanied with signs of hemoconcentration, can be seen. Extravascular position of carbon material is seldom observed and restricted to a state of abnormally high vascular permeability. The observations give evidence for a 'gradient of permeability' between the different types of vessels of the terminal anterior uveal vascular system and also permit the assumption that the vessels of the ciliary processes are more permeable than those of the iris.

動脈硬化病変の修復

Regression of experimental atherosclerosis has been introduced by some investigators. This paper represents the regression of atherosclerosis in the respect of vascular permeability, aging of aorta and the reversibility of early atherosclerotic lesions (e. g. fatty streak, cloudy thickening and mural thrombi).Ultrastructurally, aortic intima consists of three layers and increased in thickness in the aged group (over 60yrs). In this group, most remarkable change is thickening of the inner layer of intima, connective tissue layer. There are atrophy of intimal myogenic cells, extracellular basement membrane-like material deposits and proliferation of disrupted fibrillar elastic and collagen fibers. The result shows the severity of regression of atherosclerotic lesions in such an aged group because of its morphological findings.Vascular permeability of human common carotid artery by means of 1% ferric citrate infusion is presented. In the aged group, ferric citrate is condensed in the superficial zone of intima and is caught in the elastic lamina of media. It seems to be thought as the decrease of whole vascular permeability. In the advanced atherosclerotic lesions, there is a lowering of ferric citrate permeability. On the other side, initial lesions of atherosclerosis shows high vascular permeability. These findings of vascular permeability reveal that there must be complicated circumstance behind the regression of atherosclerosis.Early lesions of atherosclerosis seem to be all reversible when the lesions are not severe and the lack of irreversible destruction of intimal structure and fibro-cellular proliferation.Experimental aortic atherosclerosis of rabbit induced by cholesterol feeding for 8 weeks showed a tendency to the depletion of aortic fatty lesion 6 weeks after returning to the basal diet.And the author observed the process of organization of experimental aortic thrombi in rabbit. This complete results of experimental atherosclerosis should be reported in detail afterwards.