Heparan sulfate degradation in tumor cell invasion and angiogenesis.
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Animals↗
Biomedical subjects
A Eldor
Publications and source records attributed to A Eldor.
Decreased neutrophil thromboxane A2 and endothelial PGI2 production in the postoperative period. An in vitro assay for detection of neutrophil and plasma dysfunction.
Severe trauma results in reversible abnormalities in neutrophil function, but the specific role in the pathogenesis of postoperative sepsis is undetermined. Twenty adult patients undergoing elective surgical procedures were studied. Blood samples were obtained prior to and 24 hours after operation. Blood neutrophils were isolated and incubated (10(7) cells/mL) on bovine vascular endothelial cell monolayers. Untreated plasma or zymosan-activated plasma (ZAP) or 65 C inactivated plasma was added, and TxB2 and 6-keto PGF1 alpha production measured after 2 hours. Endothelial damage was detected by light and scanning electron microscopy beginning 2 and 4 hours after treatment. Preoperatively, neutrophil TxB2 release was less than 200 pg/mL; following ZAP it was 2153 pg/mL (p less than 0.001), with untreated plasma 1055 pg/mL (p less than 0.005) and inactivated plasma 764 pg/mL (p less than 0.01). Neutrophil TxB2 release on a plastic dish was not different from incubation on endothelium. Endothelial 6-keto PGF1 alpha release following addition of untreated plasma preoperatively was 1308 pg/mL (p less than 0.01), and with ZAP 1305 pg/mL (p less than 0.01). Activated neutrophils did not alter 6-keto PGF1 alpha production. Postoperatively, neutrophil TxB2 production in response to ZAP was 1092 pg/mL, which was significantly reduced compared to the preoperative response (p less than 0.01). Endothelial damage by activated neutrophils in the postoperative period demonstrated on scanning electron microscopy was also reduced; 6-keto PGF1 alpha release in the postoperative period inducted by ZAP was 569 pg/mL and by untreated plasma 549 pg/mL, which was significantly lower than in the preoperative period (p less than 0.05 and p less than 0.05, respectively). No difference in chemotaxis was demonstrated. It is concluded that operative trauma is followed by lowered neutrophil TxB2 release, appearance of a plasmatic factor that depresses endothelial 6-keto PGF1 alpha production, as well as decreased neutrophil-induced endothelial damage. The neutrophil-endothelial monolayer system is a sensitive method for detection of neutrophil and plasmatic dysfunction.
Adult↗
A low molecular weight brain substance interacts, similarly to clonidine, with alpha 2-adrenoceptors of human platelets.
In the present study, we explored the effects of a clonidine-displacing substance (CDS) which was isolated and partially purified from bovine brain. The low molecular weight brain substance competes with clonidine and rauwolscine in rat brain membranes, and mimics clonidine's inhibitory action in rat vas deferens. We find that CDS competes with [3H]rauwolscine-labeled alpha 2-adrenoceptors in human platelets. Further characterization of CDS in human platelets reveals that, like clonidine, it inhibits the epinephrine-induced aggregation, potentiates the ADP- and the collagen-induced aggregation however, by itself, CDS is unable to induce aggregation. Unlike clonidine, CDS does not affect the prostacyclin (PGI2)-stimulated cAMP accumulation in intact platelets. The presence of CDS in human plasma, as we have recently shown, implies a possible role of CDS in the regulation of platelet action.
Animals↗
Prevention of clot formation in cat retinal vein by systemic and subconjunctival urokinase.
The thrombolytic effect of urokinase was tested on cat retinal vein thrombus induced by argon laser photocoagulation. At various time intervals after thrombosis, intravenous infusion or subconjunctival injections were given. Subconjunctival normal saline injections were used for controls. In vitro subconjunctival urokinase prevented thrombus organization if given within six hours of thrombosis. Subconjunctival injections of urokinase vs normal saline were also studied in vivo in a masked fashion. At intervals of three to 24 hours following thrombosis, 11 cats were treated with subconjunctival urokinase in one eye and normal saline in the 11 fellow eyes. Within ten days after thrombosis, the vein was patent in eight (72%) of the 11 eyes treated with urokinase and in one (9%) of the 11 control eyes.
Animals↗
High incidence of relapses in thrombotic thrombocytopenic purpura. Clinical study of 38 patients.
Described in this study are 38 patients who received treatment for thrombotic thrombocytopenic purpura in 15 hospitals in Israel and the New York City area since 1977, when plasma therapy was introduced. Thirty-seven patients received plasma therapy and 30 survived. In 12 patients (37 percent of survivors), relapsing thrombotic thrombocytopenic purpura developed, manifested by thrombocytopenia and microangiopathic hemolytic anemia, and less frequently by neurological or renal abnormalities. Six patients had a second relapse, and two had five relapses. To assess the severity of the disease, a scoring system was designed based on the four major manifestations of thrombotic thrombocytopenic purpura listed above. The patients who died had a significantly higher score than those who survived. The initial episodes and the relapses of patients with relapsing thrombotic thrombocytopenic purpura were milder than those in patients who only had a single episode and survived. Two relapses, however, were fatal, demonstrating that relapsing thrombotic thrombocytopenic purpura is not a benign disorder. Infections, pregnancy and surgery were frequently associated with the initial episodes and the relapses. Hence, patients who recover from thrombotic thrombocytopenic purpura should be alerted to the possibility of relapse in association with these conditions.
Adult↗
Recovery of prostacyclin capacity of irradiated endothelial cells and the protective effect of vitamin C.
Ionizing irradiation has been reported to affect prostacyclin (PGI2) production by intact blood vessels and cultured endothelial cells (EC) due to damage of enzymes of the arachidonate cascade. In the present study, we investigated whether EC can recover from radiation injury and regain their capacity to produce PGI2. Bovine aortic EC were exposed to radiation doses of 3 and 6 Gy and their capacity to produce PGI2 in response to stimulation with arachidonic acid was tested, at various times after irradiation. The results of these experiments showed clearly that EC exposed to single or fractionated irradiation could recover their capacity to produce PGI2 depending on the radiation dose and the time period following radiation. Radiation damage is associated with oxidant stress and the production of free radicals. We therefore tested the ability of an oxygen radical scavenger, vitamin C, to protect the capacity of irradiated EC to produce PGI2. Pretreatment of EC with low concentrations of vitamin C inhibited the radiation induced release of PGI2 to the culture medium. Vitamin C also enhanced the capacity of irradiated EC to produce PGI2 following short stimulation with arachidonic acid. Treatment with this scavenger however, did not protect the cells against the cytopathic effects of radiation.
Animals↗
The saliva of the medicinal leech Hirudo medicinalis--II. Inhibition of platelet aggregation and of leukocyte activity and examination of reputed anaesthetic effects.
1. Leech saliva inhibits platelet aggregation induced by collagen, ADP and epinephrine. 2. Leech saliva inhibits superoxide production by neutrophils stimulated by tetradecanoyl phorbol acetate or polyhistidine. The effect is due in part at least to eglin. 3. Reputed anaesthetic effects of leech saliva were not detected.
Adenosine Diphosphate↗
Role of heparanase in platelet and tumor cell interactions with the subendothelial extracellular matrix.
Dissemination of neoplastic cells within the body involves invasion of blood vessels by tumor cells. Since platelets have been shown to contribute to this process, we studied the interaction in vitro of platelets and malignant cells with the vascular endothelium and its underlying basement membrane-like ECM. A metastatic subline (ESb) of the methylcholanthrene-induced DBA/2 T-lymphoma invaded the vascular endothelium at a higher rate than its parental nonmetastatic (Eb) subline. ESb cells also exhibited a much higher ability to degrade the proteoglycan scaffold of the ECM by means of a specific HS degrading endoglycosidase (heparanase). The interaction of platelets with this ECM was associated with platelet activation, aggregation, and degradation of HS by means of the platelet heparanase. Degradation of ECM-HS was facilitated by proteolytic activity that produced a more accessible substrate for further cleavage by heparanase. A similar enhancement was exerted by plasminogen via the activity of the tumor cells or ECM associated PAs. Heparin and chemically modified heparins that lack anticoagulant activity inhibited degradation of the ECM-HS by heparanase. Interaction of platelets and lymphoma cells with ECM covered with vascular endothelial cells was investigated by SEM and by determination of ECM-HS degradation products. SEM studies demonstrated that platelets may adhere to minor gaps between adjacent endothelial cells and degrade the ECM-HS. Platelets were also shown to recruit lymphoma cells into these interendothelial gaps, suggesting that by binding to ECM and release of heparanase, platelets may play an active role in tumor cell invasion and metastasis. Our observation that nonanticoagulant heparins may interfere with heparanase-mediated degradation of ECM-HS suggests a potential therapeutic use for such heparins in neoplastic disorders.
Animals↗
The effect and interactions of interferon and arachidonate products with vessel wall cells.
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Animals↗
Inhibition of heparanase-mediated degradation of extracellular matrix heparan sulfate by non-anticoagulant heparin species.
Incubation of human platelets, human neutrophils, or highly metastatic mouse lymphoma cells with sulfate-labeled extracellular matrix (ECM) results in heparanase-mediated release of labeled heparan sulfate cleavage fragments (0.5 less than Kav less than 0.85 on Sepharose 6B). This degradation was inhibited by native heparin both when brought about by intact cells or their released heparanase activity. Degradation of heparan sulfate in ECM may facilitate invasion of normal and malignant cells through basement membranes. The present study tested the heparanase inhibitory effect of nonanticoagulant species of heparin that might be of potential use in preventing heparanase mediated extravasation of bloodborne cells. For this purpose, we prepared various species of low-sulfated or low-mol-wt heparins, all of which exhibited less than 7% of the anticoagulant activity of native heparin. N-sulfate groups of heparin are necessary for its heparanase inhibitory activity but can be substituted by an acetyl group provided that the O-sulfate groups are retained. O-sulfate groups could be removed provided that the N positions were resulfated. Total desulfation of heparin abolished its heparanase inhibitory activity. Heparan sulfate was a 25-fold less potent heparanase inhibitor than native heparin. Efficiency of low-mol-wt heparins to inhibit degradation of heparan sulfate in ECM decreased with their main molecular size, and a synthetic pentasaccharide, representing the binding site to antithrombin III, was devoid of inhibitory activity. Similar results were obtained with heparanase activities released from platelets, neutrophils, and lymphoma cells. We propose that heparanase inhibiting nonanticoagulant heparins may interfere with dissemination of bloodborne tumor cells and development of experimental autoimmune diseases.
Animals↗
Hemorrhagic shock prevents lung microvascular permeability and hypoxemia associated with complement activation in the awake sheep.
The effect of hemorrhagic hypotension on pulmonary dysfunction induced by complement activation was studied in 43 awake sheep, divided into six groups: Group I (n = 6), pulmonary vascular pressure was increased by inflation of a left atrial balloon; group II (n = 9), the complement system was activated by infusion of zymosan activated plasma (ZAP); group III (n = 5), hemorrhagic shock of 50 torr was induced for 3 hr; group IV (n = 10), hemorrhagic shock was induced as in group III, and after 2 hr of shock, ZAP was infused; group V (n = 8), 5 mg/kg of indomethacin was administered before ZAP infusion; group VI (n = 5), pretreatment with indomethacin as in group V, hemorrhagic shock and ZAP as in group IV. ZAP infusion in group II led to a fall in WBC to 2,600/ml (P less than 0.001), and a rise in mean pulmonary artery pressure to 41.1 torr (P less than 0.001) and in pulmonary shunting (QS/QT) to 29.4% (P less than 0.001). Arterial oxygen tension (PaO2) fell to 62.0 torr (P less than 0.001), pulmonary lymph flow (QL) rose to 14.0 ml/hr (P less than 0.01), and lymph protein clearance (L/P.QL) to 8.9 ml/hr (P less than 0.01). Plasma thromboxane B2 (TxB2) increased to 2.43 ng/ml (P less than 0.025) and pulmonary lymph TxB2 to 3.02 ng/ml (P less than 0.005). Hemorrhagic shock was followed by a rise in PaO2 to 97.5 torr (P less than 0.01), a fall in QS/QT to 7.9% (P less than 0.005), QL to 5.0 ml/hr (P less than 0.05), and L/P QL to 2.9 ml/hr (P less than 0.05). During hemorrhage, plasma TxB2 rose to 2.18 ng/ml (P less than 0.005) and lymph TxB2 to 2.32 ng/ml (P less than 0.001). Infusion of ZAP during hemorrhagic shock was followed by a fall in WBC to 2,300/microliter (P less than 0.001); but QS/QT, PaO2, QL, and L/P.QL remained unchanged. After indomethacin and ZAP, WBC fell to 3,210/microliter (P less than 0.001), Ppa rose to 27.0 torr (P less than 0.05), QL rose to 8.3 ml/hr (P less than 0.05), and L/P.QL rose to 5.2 ml/hr (P less than 0.05). PaO2 fell to 75.0 torr (P less than 0.05) and QS/QT increased to 17.1% (P less than 0.005). The protective effect of hemorrhagic shock on ZAP-induced pulmonary dysfunction was not reversed by indomethacin. It is concluded that hemorrhagic shock prevents hypoxemia and increased pulmonary permeability induced by activation of the complement system by ZAP.
Animals↗
Different effects of aspirin, dipyridamole and UD-CG 115 on platelet activation in a model of vascular injury: studies with extracellular matrix covered with endothelial cells.
Cultured endothelial cells produce an extracellular matrix (ECM) which activates platelets, similarly to deendothelialized vascular segments. Platelet-rich plasma (PRP) was incubated with endothelial cells cultures seeded in various densities on ECM. The interaction of the platelets with this artificial intima was evaluated by phase microscopy and by thromboxane A2 (TXA2) and prostacyclin (PGI2) measurement. Large platelet aggregates were formed on exposed ECM. Platelets aggregation but not adhesion on the ECM was markedly inhibited by the presence of endothelial cells. Pretreatment of the endothelial cells with 0.1 mM aspirin reduced their PGI2 synthesis and was associated with platelet aggregation on the ECM. 10 microM dipyridamole markedly inhibited platelet activation by ECM when the drug was added to citrated whole blood before PRP preparation. UD-CG 115 which elevates cyclic AMP in cardiac muscle, inhibited platelet aggregation and TXA2 production induced by ECM, in the presence as well as in the absence of endothelial cells, without any effect on endothelial PGI2 production.
6-Ketoprostaglandin F1 alpha↗
Pulmonary valve stenosis and hemophilia A. Report of three cases and discussion of a possible genetic linkage.
We treated three unrelated patients with hemophilia A and congenital pulmonary valve stenosis. In two patients, the occurrence of the cardiac malformation was sporadic and in one familial. The coexistence of hemophilia A and pulmonary valve stenosis might suggest a genetic linkage for both disorders. Review of the literature supports the hypothesis that the inheritance of pulmonary valve stenosis is dominant and X-linked.
Adolescent↗
The mean platelet volume (MPV) in the neonatal period.
Previous studies in adults have demonstrated that the mean platelet volume (MPV), which is now routinely measured during blood counting performed by the Coulter Counter S Plus, is an important parameter and may serve as a predictor of the hemostatic potential of patients with severe thrombocytopenia. MPVs and platelet counts were determined in 155 neonates in order to establish the normal values of the mean platelet volume during the neonatal period. Analysis of variance performed in 119 neonates of birthweight greater than 2 kg revealed a significant rise with age of both platelet count (P less than 0.0001 and MPV (P less than 0.02) during the neonatal period. The platelet counts of these 119 neonates (323336 +/- 106918; mean +/- SD) were significantly higher (P less than 0.05) than the platelet counts (283805 +/- 114130) of 36 neonates where birthweight was less than 2 kg. There was no significant difference between the MPV values of the two groups (8.67 +/- 1.03 micron3 and 8.89 +/- 1.10 micron3, respectively). Since increased MPV is observed during periods of platelet production, the above results suggest that the rise of platelet count associated with increased MPV in newborn infants is due to increased production of platelets in the early postnatal weeks.
Birth Weight↗
Intracranial hemorrhage in patients with hemophilia.
Intracranial hemorrhage (ICH) is a life-threatening complication of hemophilia. Seven of the 288 hemophiliacs living in Israel suffered eight episodes of ICH during the years 1972 to 1982. All episodes occurred in hemophilia A patients, with a higher incidence among patients with factor VIII inhibitor. Diagnosis was confirmed by computed tomographic scan in seven of the eight episodes. Four of the 7 patients died despite adequate factor replacement and supportive therapy, probably due to a conservative and hesitant neurosurgical approach. The correction of factor VIII to hemostatic level alone is inadequate in the majority of cases, and there is sudden deterioration in the patient's condition and death. Operation is strongly recommended when no improvement is noted within a few hours.
Adult↗
Megakaryocyte interaction with the subendothelial extracellular matrix.
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Animals↗
Adhesion, spreading and fragmentation of human megakaryocytes exposed to subendothelial extracellular matrix: a scanning electron microscopy study.
Platelet agonists and subendothelial extracellular matrix (ECM) induce morphological and biochemical changes in animal megakaryocytes, reminiscent of the response of platelets to the same substances. We have examined the behavior of human megakaryocytes exposed for up to 36 hours to the ECM produced by cultured bovine corneal endothelial cells. By phase contrast and scanning electron microscopy these megakaryocytes demonstrated non-reversible adherence and flattening with formation of long filopodia, thus confirming that human megakaryocytes acquire platelet functional capacities. In addition, megakaryocyte fragmentation into prospective platelets was apparently induced by the ECM. Up to 50% of the adherent megakaryocytes underwent spontaneous fragmentation into small particles which individually reacted like platelets on the ECM. The interaction of the megakaryocytes with the ECM was specific since no adherence, flattening or fragmentation occurred upon incubation of the megakaryocytes on regular tissue culture plastic or glutaraldehyde fixed ECM. Thus we have demonstrated platelet like behaviour of human megakaryocytes in response to this physiological basement membrane and a possible role of the subendothelium in platelet production which may occur in vivo as megakaryocytes cross the sinusoid walls and enter the blood stream.
Animals↗