Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblastoid synovial lining cells isolated from rheumatoid and other chronic inflammatory synovial tissue exhibit distinctive and sustained alterations in serial culture not commonly found in similarly cultured cells from osteoarthritic synovium. These are demonstrable using a multi-gene dot blot assay by labelling reverse transcribed fibroblast cDNA which is hybridized to plasmids containing relevant target gene inserts. Cultured synovial fibroblastoid cells from patients with chronic inflammatory synovitis expressed significantly higher levels of stromelysin, vimentin and TIMP-1 mRNA and lower levels of c-myc compared to cells isolated from osteoarthritis synovium although with considerable variation. Early fetal synovial lining cells were similar to cells from osteoarthritis synovium but vimentin expression was higher. Marked differences in patterns of gene expression between cell lines persisted through 10 serial passages over 6-8 months. In whole synovia, the average level of mRNA for stromelysin, vimentin, IL-4, IL-6, TIMP-1, cathepsin D, gelatinase, TGF alpha, c-fms and DR beta were preferentially expressed in inflammatory tissue while c-myc expression was higher in osteoarthritis synovium. Inflammatory synovium also expressed TNF alpha, IL-1 alpha, IL-1 beta, IL-2, c-sis, tissue plasminogen activator, CSF-1, and GM-CSF. This pattern resembles, in part, that found in cultured inflammatory fibroblasts but, in addition, gene products apparently reflecting the presence of activated monocytes and lymphocytes were detected. These results provide evidence that profiles of certain gene activation in cells from patients with inflammatory synovitis differ from those with non-inflammatory disease and suggest that the fibroblastoid cells are responsible for a considerable proportion of the altered phenotypic expression pattern in whole tissue. Furthermore, this modulated pattern of gene activation appears to be an intrinsic pro-inflammatory characteristic of the fibroblastoid cells initiated in response to chronic inflammation and persists for a prolonged period in the absence of other inflammatory cells.
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PMID:Sustained and distinctive patterns of gene activation in synovial fibroblasts and whole synovial tissue obtained from inflammatory synovitis. 809 Nov 28

We determined that exposure of cultured lung fibroblasts (HEL-299) to recombinant human interleukin-6 (0-400 ng/ml) resulted in a dose- and time-dependent increase in secreted and cell lysate PAI-1 and total tPA levels (maximal increase of 2.6-fold and 1.7-fold, respectively). Specificity of this response was indicated when increases in PAI-1 levels were inhibited by neutralizing polyclonal antibodies to IL-6, but not with non-specific antibodies. Inhibition of the response to IL-6 by cycloheximide and alpha-amanitin indicates that increases in PAI-1 are dependent on both protein and RNA synthesis. The addition of IL-6 to HEL-299 cells also stimulated a dose- and time-dependent increase in steady-state PAI-1 mRNA levels (3.8 to 15.1 pg/micrograms total RNA by 24 h). A rapid increase (5-6-fold) in PAI-1 mRNA levels was found between 3 and 12 h. Nuclear run-on assays using a maximum dose of IL-6 showed that IL-6 increases a 4-fold rate of transcription of the PAI-1 gene. We further showed that LPS induces a 70% increase in secreted IL-6 and a 50% increase in PAI-1 protein levels. Increasing doses of anti-IL-6 completely blocked the effect of LPS on PAI-1 while non-specific antibodies had no effect. These studies suggest an autocrine role for IL-6 in regulating localized proteolysis and modulating tissue remodeling during acute inflammatory conditions by fibroblasts.
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PMID:Regulation of plasminogen activation by interleukin-6 in human lung fibroblasts. 816 53

Abnormal cytokine levels have been described in patients with chronic liver disease, but studies correlating cytokine homeostasis with abnormalities in coagulation and fibrinolysis are lacking. In order to establish a link between cytokines and the hemostatic changes the following parameters were determined in 44 patients with cirrhosis (alcoholic = 15, postnecrotic = 22, others = 7): TNF-alpha, IL-6, thrombin-antithrombin (TAT) complexes, prothrombin fragment 1 + 2 (F1 + 2) and t-PA by using enzyme-linked immunosorbent assays, and PAI-1, plasminogen and alpha 2-antiplasmin (alpha 2-AP) by using chromogenic substrates. All patients were at stages B and C of Child's classification when entering the study. Mean cytokine concentrations were significantly higher in cirrhotic patients as compared to age- and sex-matched controls (p < 0.009). There was a significant increase of TAT (p < 0.02) and F1 + 2 (p < 0.001) in the patients groups, suggesting a grade of intravascular coagulation. A hyperfibrinolytic state as demonstrated by an increase of t-PA and decrease of plasminogen and alpha 2-AP was also observed (p < 0.001). We could define a subgroup of patients with cytokine values higher than 20 pg/ml. Interestingly, in this group there was a significant increase of TAT (p < 0.04) and t-PA (p < 0.02) levels and a decrease of plasminogen and alpha 2-AP (p < 0.02) as compared to values observed in patients with cytokines lower than 20 pg/ml. We conclude that high levels of TNF-alpha and IL-6 may contribute to hyperfibrinolysis and intravascular coagulation in patients with liver cirrhosis, as assessed by the increase of TAT and t-PA levels and the reduction of plasminogen and alpha 2-AP.
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PMID:Increased concentrations of tumor necrosis factor and interleukin-6 contribute to the hemostatic abnormalities in advanced liver disease. 858 22

IL-10 protects mice from LPS-induced lethality. To determine the effects of IL-10 on LPS-induced inflammatory responses, six Papio anubis baboons were i.v. injected with a sublethal dose of LPS (Salmonella typhimurium; 500 microg/kg) directly preceded by either human rIL-10 (n = 3, 500 microg/kg) or diluent (n = 3). IL-10 strongly inhibited LPS-induced release of TNF, IL-6, IL-8, and IL-12 (all p < 0.05). By contrast, IL-10 did neither influence the activation of the coagulation system (plasma levels of thrombin/antithrombin III complexes), nor the activation of the fibrinolytic system (plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor type I, and plasmin/alpha 2-antiplasmin complexes). IL-10 modestly attenuated neutrophilic leukocytosis and neutrophil degranulation (plasma concentrations of elastase/alpha1-antitrypsin complexes) (both p < 0.05). Changes in surface TNF receptor expression on circulating granulocytes were not affected by IL-10. These results suggest that during sublethal endotoxemia the predominant anti-inflammatory effect of IL-10 treatment is inhibition of proinflammatory cytokine release.
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PMID:Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia. 902 40

Although the severity of periodontal disease is known to be affected by age, functional changes of periodontal tissue cells during the aging process are not well characterized. It is important to define how cellular aging affects the progression of periodontal diseases associated with the aging process. In vitro aging of human gingival fibroblast (HGF) and periodontal ligament fibroblast (HPLF) cells was prepared by sequential subcultivations (5 to 6 passages as young, 18 to 20 passages as old). GFs were also prepared from gingiva of Down's syndrome patients and 60-week-old rats. Fetal rat calvarial osteoblasts were prepared by sequential digestion with collagenase. HGF and HPLF cells were treated with lipopolysaccharide (LPS) and cyclic tension force, respectively. Amounts of PGE2, interleukin (IL)-1 beta, IL-6, and plasminogen activator (PA) in conditioned media were measured. Total RNA was extracted, and mRNA expression was analyzed by reverse transcription polymerase chain reaction (RT-PCR). LPS-stimulated PGE2, IL-1 beta, IL-6, and PA production was increased in "old" HGF compared to younger cells. According to RT-PCR analysis, gene expression of COX-2, IL-1 beta, IL-6, and tissue type (t) PA was higher in old cells than in young cells. Cyclic tension force to HPLF also stimulated phenotypic and gene expression of IL-1 beta, PGE2 (COX-2 gene) and tPA. These findings suggest that aging in both HGF and HPLF may be an important factor in the severity of periodontal disease through higher production of inflammatory mediators in response to both LPS and mechanical stress. In addition, oxygen radical-treated fibronectin (FN) as substratum diminished bone nodule formation by osteoblasts when compared with intact FN. This finding suggests that FN plays an important role in Osteoblast activity and that FN damaged by oxygen radicals during the aging process may be related to less bone formation.
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PMID:Effect of aging on functional changes of periodontal tissue cells. 972 19

Glomerular fibrin deposition is thought to be one of the factors causing progressive glomerular injury and may be related to defective intraglomerular fibrinolysis. Recently, it was shown that tissue plasminogen activator (t-PA) is produced by mesangial cells and is associated with degradation of the extracellular matrix. This study was designed to clarify the factors regulating t-PA production in human mesangial cells. The levels of t-PA activity, t-PA antigen and t-PA inhibitor-1 (PAI-1) antigen were estimated in the supernatants of cultured human fetal mesangial cells incubated for 72 h with thrombin, IL-Ibeta, IL-6, IL-10, and transforming growth factor-beta (TGF-beta). The t-PA activity was measured by an amidolytic assay, and the levels of t-PA antigen and PAI-1 antigen were also measured by enzyme-linked immunosorbent assay. Thrombin increased t-PA activity and TGF-beta decreased it in parallel with t-PA antigen level, although these agents did not affect the synthesis of PAI-1. Incubation with IL-1beta, IL-6 and IL-10 did not change the t-PA activity. It was concluded that the release of t-PA from human fetal mesangial cells was stimulated by thrombin and inhibited by TGF-beta in parallel with that of t-PA antigen. These factors may participate in the glomerular fibrin deposition and the accumulation of extracellular matrix.
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PMID:Regulation of tissue plasminogen activator production in cultured human fetal mesangial cells. 980 22

Inflammatory response in tissue results from a complex network of interactions between inflammatory cells (mast cells, eosinophils, basophils, macrophages) and resident cells belonging to the lung structure (like endothelial cells, fibroblasts, epithelial cells). Among structural cells, endothelial cells play a critical role. The important role of endothelium is also reflected in the fact that it occupies an area exceeding 1000 m2. Thus, endothelium is the largest and the most active paracrine organ in the body, producing potent vasoactive, procoagulant, anticoagulant, and proinflammatory substances. Endothelial cells have four key functions that alter in the process of inflammation: 1 a) Regulation and control of leukocyte traffic through the expression of adhesion molecules (selectins E and P, molecules of immunoglobulin superfamily ICAM-1, ICAM-2, VCAM); 1 b) They are also able to amplify leukocyte activation through the production of proinflammatory cytokines like IL-1, IL-6 and chemokines like IL-8 and RANTES molecules; 2) Regulation of vascular tone by production of PGI-2, EDRF/NO and elements of local renin-angiotensin system; 3) Regulation of local coagulation by controlling the production of t-PA and PAI-1; 4) Regulation of the vascular permeability. In the states of acute inflammation, the endothelial cell takes on a proinflammatory phenotype and as such becomes chemoattractant, facilitating leukocyte adhesion, activation and migration, becomes prothrombotic and demonstrates enhanced vascular permeability.
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PMID:[The role of endothelial cells in allergic inflammation reactions]. 986 70

To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever (temperature above 38.0 degrees C axillary or 38.3 degrees C rectally), and daily thereafter for two days, circulating thrombin-antithrombin III (TAT) complexes, plasmin-alpha2-antiplasmin (PAP) complexes (day 0 only), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and interleukin (IL)-6, the latter as a marker of the inflammatory host response. Study variables were 1) positive microbiological results for specimens from local sites associated with a clinical infection, positive blood cultures (including parasitemia) or both, within 7 days after inclusion, 2) development of shock, i.e. systolic blood pressure <90 mmHg or a reduction of 40 mmHg from baseline within 7 days after inclusion, and 3) death related to febrile illness within 28 days after inclusion. The peak plasma levels of TAT complexes were elevated in 44% and the PAP complexes in all patients. The t-PA and PAI-1 levels were elevated in 74 and 94% of patients, respectively. Values for TAT and PAP did not differ among subgroups, while peak t-PA and IL-6 levels were higher in patients with positive microbiological results, developing shock or ultimately dying than in those without the complications (p<0.005). Peak PAI-1 levels were elevated in patients developing shock and ultimate death versus those with an uncomplicated course (p <0.05). Peak IL-6 related to PAI-1 and t-PA levels, which interrelated. Patients with elevated TAT levels had increased plasma levels of IL-6, PAP, PAI-1 and t-PA versus those with normal TAT (p <0.05). Our data indicate that inhibition of activated fibrinolysis, which may partly depend on both cytokinemia and activation of coagulation, predicts microbial infection, septic shock and mortality of febrile medical patients. This suggests an early pathogenic role of inhibition of activated fibrinolysis in the downhill course of serious microbial infection.
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PMID:Early inhibition of activated fibrinolysis predicts microbial infection, shock and mortality in febrile medical patients. 1152 1

Dengue virus infection causes dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), whose pathogeneses are not clearly understood. Current hypotheses of antibody-dependent enhancement, virus virulence, and IFN-gamma/TNFalpha-mediated immunopathogenesis are insufficient to explain clinical manifestations of DHF/DSS such as thrombocytopenia and hemoconcentration. Dengue virus infection induces transient immune aberrant activation of CD4/CD8 ratio inversion and cytokine overproduction, and infection of endothelial cells and hepatocytes causes apoptosis and dysfunction of these cells. The coagulation and fibrinolysis systems are also activated after dengue virus infection. We propose a new hypothesis for the immunopathogenesis for dengue virus infection. The aberrant immune responses not only impair the immune response to clear the virus, but also result in overproduction of cytokines that affect monocytes, endothelial cells, and hepatocytes. Platelets are destroyed by crossreactive anti-platelet autoantibodies. Dengue-virus-induced vasculopathy and coagulopathy must be involved in the pathogenesis of hemorrhage, and the unbalance between coagulation and fibrinolysis activation increases the likelihood of severe hemorrhage in DHF/DSS. Hemostasis is maintained unless the dysregulation of coagulation and fibrinolysis persists. The overproduced IL-6 might play a crucial role in the enhanced production of anti-platelet or anti-endothelial cell autoantibodies, elevated levels of tPA, as well as a deficiency in coagulation. Capillary leakage is triggered by the dengue virus itself or by antibodies to its antigens. This immunopathogenesis of DHF/DSS can account for specific characteristics of clinical, pathologic, and epidemiological observations in dengue virus infection.
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PMID:Immunopathogenesis of dengue virus infection. 1154 79

In a prospective clinical study of 50 patients with Dengue Shock Syndrome (DSS), we investigated the association of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), and IL-6 with activation markers of coagulation (F1+2 and TATc) and fibrinolysis (t-PA, PAPc, and D-dimer). We found that TNF-alpha, IL-1beta and Il-1Ra, but not IL-6, concentrations were elevated in the circulation during the early stage of infection and at discharge from hospital. TNF-alpha was significantly associated with D-dimer, an activation marker of fibrinolysis (p < 0.003), but not with activation markers of coagulation. IL-1beta was significantly associated with t-PA (p < 0.03). IL-1Ra was significantly associated with F1+2, TATc (p < 0.04 and p < 0.02, respectively), whereas IL-6 was significantly associated with both, activation markers of coagulation (F1+2; p < 0.03) and fibrinolysis (PAPc; p = 0.002). Our data are in line with studies in bacterial sepsis. In severe dengue virus infection the same cytokines are involved in the onset and regulation of hemostasis.
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PMID:The role of cytokines in activation of coagulation and fibrinolysis in dengue shock syndrome. 1185 87


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