Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interaction of proteases with cell surface receptors may modulate cell adhesion, migration, invasion, and matrix degradation. Since the plasminogen activator system has been hypothesized to play a role in intimal thickening after various types of vascular injury, we first studied the expression of urokinase receptor (u-PAR) protein and mRNA by smooth muscle cells (SMC) grown in explant cultures from normal and diseased vessels. Using equilibrium binding studies with radiolabeled 125I-labeled single chain urokinase-type plasminogen activator (scu-PA), we determined that SMC cultured from atherosclerotic arteries expressed a higher maximal number of binding sites/cell (3.6 +/- 0.4 x 10(5) sites/cell vs. 2.1 +/- 0.3 x 10(5), +/- SEM, p < 0.05) with a similar affinity (Kd = 1.5 +/- 0.1 vs. 1.2 +/- 0.2 nM, p = ns). However, SMC subcultured from diseased saphenous vein grafts expressed the highest levels of u-PAR compared to SMC from normal saphenous vein (4.8 +/- 0.6 x 10(5) sites/cell vs. 1.6 +/- 0.9 x 10(5), +/- SEM, p < 0.05). Using binding studies and Northern analysis, we demonstrated a dose and time dependent upregulation of u-PAR protein and mRNA expression respectively in human SMC in response to serum stimulation. Using a rabbit specific u-PAR cDNA probe, we demonstrated a similar upregulation of u-PAR mRNA both in rabbit aortic SMC in culture in response to serum stimulation and up to a 20 fold increase in u-PAR mRNA in rabbit jugular veins in response to implantation as arterial grafts in vivo. Finally, to confirm that u-PAR mRNA is upregulated in human vessels after injury, we performed immunohistochemistry and in situ hybridization studies on coronary arteries, normal saphenous veins and saphenous veins from 10 weeks to 13 years after implantation as grafts. u-PAR mRNA was found mainly in the periadventitial microcirculation in normal veins, but was found to be upregulated in the neointima and media of thickened veins in both macrophages and smooth muscle cells. SMC near the internal elastic laminae in diseased coronary arteries appeared to express increased u-PAR mRNA. These data suggest that this increased expression of u-PAR may contribute to early lesion development.
 ...
PMID:Native atherosclerosis and vein graft arterialization: association with increased urokinase receptor expression in vitro and in vivo. 968

Butyrate may have paradoxical effects on epithelial cells of similar origin. This study aimed to examine the hypothesis that one mechanism that dictates a cell's response to butyrate is its state of activation. First, the responses to 24 h exposure to butyrate (1-2 mM) of normal and neoplastic human colonic epithelial cells activated by their isolation and primary culture, and of colon cancer cell lines, LIM1215 and Caco-2, were examined. In primary cultures of normal and cancer cells, butyrate had no effect on alkaline phosphatase activities but significantly suppressed urokinase receptor expression by a mean +/- SEM of 30 +/- 12% and 36 +/- 9%, respectively. Interleukin-8 secretion was suppressed by 44 +/- 7% in normal cells (P < 0.05) but was unchanged in cancer cells. In contrast, the cell lines significantly increased alkaline phosphatase activities by >50%, urokinase receptor expression >2-fold and interleukin-8 secretion >3-fold in response to butyrate. Secondly, the effect of butyrate on Caco-2 cells was examined with or without prior exposure to a specific activating stimulus [tumour necrosis factor alpha (TNF alpha)]. Interleukin-8 secretion increased by 145 +/- 23% and 132 +/- 17% on 24 h exposure to 2 mM butyrate or 0.1 microM TNF alpha alone, respectively. However, in cells pre-treated with TNF alpha, butyrate significantly inhibited secretion by 34 +/- 7% below unstimulated levels. The response to butyrate of urokinase receptor, whose expression was not stimulated by TNF alpha, was unchanged. These effects were mimicked by trichostatin A, an inhibitor of histone deacetylase, suggesting that butyrate's paradoxical effects may have been operating by the same mechanism. In conclusion, some of the paradoxical effects of butyrate do not appear to represent inherent differences between normal and transformed cells. Rather, the response may be determined by the state of activation of the cells.
 ...
PMID:Colonic epithelial cell activation and the paradoxical effects of butyrate. 1022 79

During acute and chronic inflammatory lung diseases, the normal fibrinolytic activity in the alveolar space is inhibited by increased levels of plasminogen activator inhibitor 1 (PAI-1). Transgenic mice having increased fibrinolytic activity due to genetic deficiency of PAI-1 develop less fibrosis after bleomycin-induced lung inflammation. These observations led us to hypothesize that pulmonary fibrosis could be limited through enhancement of alveolar fibrinolytic activity by adenovirus-mediated transfer of the urokinase-type plasminogen activator (uPA) gene to the lung. To investigate this hypothesis, 0.075 U of bleomycin was introduced intratracheally into mice. Twenty-one days later, the mice were treated intratracheally with phosphate-buffered saline (PBS), a control adenovirus, or adenoviruses containing murine or human uPA cDNAs. On day 28, the mice were sacrificed, and lung fibrosis was quantitated by measuring hydroxyproline content. As expected, bleomycin caused a doubling in lung hydroxyproline to 345.6+/-28.2 microg/lung (SEM) compared with mice receiving PBS (170.2+/-4.0 microg/lung). Treatment of the bleomycin-injured mice with the control adenovirus on day 21 had no impact on lung fibrosis (338.4+/-17.2 microg/lung). Importantly, the human uPA adenovirus significantly reduced (p<0.05) lung hydroxyproline (281.2+/-22.8 microg/lung), thus attenuating by 38% the bleomycin-induced increase in lung collagen. The improvement in bleomycin-induced lung fibrosis resulting from treatment with the human uPA adenovirus further supports the importance of the fibrinolytic system during inflammatory lung injury and repair.
 ...
PMID:Treatment of bleomycin-induced pulmonary fibrosis by transfer of urokinase-type plasminogen activator genes. 1051 51

The objective of this study was to compare the therapeutic benefit of thrombolytic therapy in women and men with acute pulmonary embolism. Data were combined from five prospective multicenter trials studying the efficacy and safety of pulmonary embolism thrombolysis. The study was conducted in 34 tertiary care medical centers in the United States, Canada, and Italy. Three hundred and twelve patients (144 women and 168 men) diagnosed with pulmonary embolism by either pulmonary angiography or a combination of high-probability ventilation-perfusion scanning and high clinical suspicion with no contraindications to thrombolytic therapy were included. A thrombolytic agent (either tissue plasminogen activator or urokinase) followed by intravenous heparin was administered. The magnitude of improvement on follow-up ventilation-perfusion scans and pulmonary angiograms and the frequency of important bleeding episodes were measured. The degree of reperfusion with thrombolysis as measured by lung perfusion scanning (mean +/- SEM, 11 +/- 1% in women vs. 12 +/- 1% in men, P = 0.67), improvement in angiographic scores (1.46 +/- 0.17 vs. 1.51 +/- 0.16, P = 0.85), and decrease in mean pulmonary arterial pressures (1.8 +/- 1.0 mmHG vs. 1.3 +/- 0.7 mmHG, P = 0.70) demonstrated little difference between the two genders. In addition, the occurrence of important bleeding was similar in women and men (17% vs. 22%, P = 0.23). In conclusion, the benefits and risks posed by thrombolysis for pulmonary embolism are similar in magnitude for women and men. Therefore, patient gender should not influence the decision to treat pulmonary embolism patients with thrombolytic agents.
 ...
PMID:Similarity in Presentation and Response to Thrombolysis Among Women and Men with Pulmonary Embolism. 1076 2

The aims of this study were to examine the effect of oxygen, in the presence or absence of exogenous growth factors, on the release of plasminogen activators and plasminogen activator inhibitor-1 by cultured human retinal pigment epithelial cells. Antigen and activity levels of urokinase, tissue plasminogen activator and plasminogen activator inhibitor were measured in conditioned media after cells were exposed to three different oxygen environments: hypoxia, normoxia and hyperoxia. Overall proteolytic balance was determined by zymography. The effects of exogenous basic fibroblast growth factor and transforming growth factor-beta were also examined. it was found that retinal pigment epithelial cells released urokinase, tissue plasminogen activator and plasminogen activator inhibitor in measurable quantities. After 48 h, urokinase levels were highest at normoxia, reaching 7.2ng/10(6) cells (+/-2.0 SEM), whereas plasminogen activator inhibitor 1 levels were highest at hyperoxia, reaching 67.5ng/10(6) cells (+/-3.7 SEM). Tissue plasminogen activator levels were minimal (<0.5ng/10(6) cells) and unaffected by both oxygen and growth factors. Overall proteolytic activity was also greatest at normoxia. Fibroblast growth factor stimulated urokinase production dose-dependently, but plasminogen activator inhibitor only minimally. Transforming growth factor-beta stimulated plasminogen activator inhibitor production dose-dependently but urokinase only at higher concentrations. These results suggest that both oxygen tension and growth factors may interact to modulate the proteolytic properties of the human retinal pigment epithelium.
 ...
PMID:Oxygen modulates the release of urokinase and plasminogen activator inhibitor-1 by retinal pigment epithelial cells. 1131 55

Recent data suggest that mast cells (MCs) and their products are involved in the pathophysiology of thrombosis. In the present study, we analyzed the number, distribution, and phenotype of prostate MCs and periprostatic MCs in patients with unilateral periprostatic vein thrombosis (PVT) by immunohistochemical analysis and electron microscopy. MCs reacted with monoclonal antibodies to tryptase, chymase, and c-kit/CD117 and stained positively for tissue-type plasminogen activator (tPA) and urokinase receptor (uPAR/CD87) but did not express detectable urokinase (uPA) or plasminogen activator inhibitors (PAI-1, PAI-2). We found an increase in the mean +/- SEM number of MCs in PVT compared with control (PVT, 14.36 +/- 1.57 vs control, 5.23 +/- 0.57/mm2). The majority of MCs accumulated in the adventitia of thrombosed veins and showed a decrease in chymase expression. As MCs increase in number in PVT and express a profibrinolytic phenotype, we hypothesize that MC-derived molecules have a role in endogenous fibrinolysis.
 ...
PMID:Characterization of human prostate mast cells and their increase in periprostatic vein thrombosis. 1144 59

Clinical studies have shown that the treatment of ischemic stroke with hypothermia is promising. In this animal study, we investigated the fate of the microvasculature following focal cerebral ischemia in mice with and without hypothermia. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery (MCAO) (3 h) with an intraluminal filament technique. Eight mice received normothermia (36.5 degrees C, NT) and eight received hypothermia (32-34 degrees C, HT) treatment during 24 h of reperfusion. Another six mice represented the sham group. Analysis of the hypothermic group in comparison to the normothermic group revealed a significantly reduced infarct volume (NT: 63.56+/-4.62 mm3 SEM, HT: 38.09+/-4.83 mm3 SEM; P<0.01) and showed considerably ameliorated neurological deficits (Garcia-score) after 24 h (P<0.01). In addition, the degradation of the microvascular basal lamina antigen collagen type IV after normothermia was strongly reduced (P<0.05) compared to sham. Hypothermia diminished this effect so that collagen type IV was not significantly reduced compared to sham. Moreover the hemoglobin extravasation was strongly reduced under hypothermic treatment compared to the normothermic group (P<0.01). In the hypothermia group the urokinase plasminogen-activator (uPA) activity (P=0.01) was significantly decreased compared to the normothermia group. Also MMP-9 was significantly reduced (P<0.05) during hypothermic treatment. In conclusion, for the first time we show in mice that hypothermia preserves the microvascular wall structures after ischemia. We have demonstrated that hypothermia protects the basal lamina, reduces the infarct volume and hemorrhage, and reduces proteolytic enzymes. These protective effects in an additional animal model of ischemia and reperfusion strongly recommend hypothermia as a potential beneficial treatment for stroke.
 ...
PMID:Protection of cerebral microvasculature after moderate hypothermia following experimental focal cerebral ischemia in mice. 1858 14


<< Previous 1 2 3 4