Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF alpha) has been proposed as a mediator of endotoxin-induced lung injury. When given to sheep, TNF alpha mimics endotoxin (LPS) causing hypoxemia, pulmonary hypertension, leukopenia, reduced dynamic compliance (Cdyn), increased resistance to airflow (RL), exudation of lung lymph, and enhanced airway reactivity. TNF alpha also induces rapid release of thromboxane A2 (TxA2), prostaglandin E2 (PGE2), and prostacyclin (PGI2). We hypothesized that the inflammatory effects of TNF alpha are due at least in part to cyclooxygenase products, and therefore cyclooxygenase inhibition would have similar effects on TNF alpha-induced lung injury as has previously been demonstrated for LPS-induced lung damage. Using awake sheep with chronic lung lymph fistulas, we measured Cdyn, RL, and FRC using a whole-body plethysmograph. Pulmonary artery (Ppa), left atrial (PLA), and systemic arterial (Psa) pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples (for prostanoid levels) were collected every 30 min. Eleven animals underwent paired random-order experiments receiving ibuprofen (14 mg/kg) 1 h before human recombinant TNF alpha (10 micrograms/kg), or an identical dose of TNF alpha alone. Within 15 min of initiating TNF alpha, Ppa doubled and remained elevated for 4 h. Ibuprofen prevented the early rise in Ppa after TNF alpha. In the group receiving TNF alpha alone, increases in Ppa were accompanied by a 60% decline in leukocyte count and a 50% increase in AaPo2 within 30 min. Ibuprofen prevented increases in AaPo2, but it had no effect on leukopenia or late increases in lymph flow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of cyclooxygenase products in lung injury induced by tumor necrosis factor in sheep. 154 45

Interleukin-1 (IL-1) release from monocyte-macrophages (Mo) appears dependent on pericellular proteolysis mediated by plasmin. Thus plasminogen activator inhibitors (PAI) which bind the serine proteases responsible for the conversion of plasminogen to plasmin, may inhibit IL-1 release from Mo. We have examined the effect of purified PAI from a hepatoma cell line Hep G2, on IL-1 release from Mo with secondary effects on lymphocyte proliferation in vitro. Fast acting inhibitors of both urokinase (u-PA) and tissue plasminogen activator (two chain t-PA) were noted in harvest fluids of Hep G2 cells. These inhibitors were stable at pH 3 but lost activity at 45 degrees C. They were SDS-stable and migrated with Mr53 and 104 kDa. These properties conformed to characteristics of type-1 plasminogen activator inhibitor (PAI-1). Partially purified PAI-1 added to human Mo cultured on 125I fibrin layer both in the presence and absence of plasminogen inhibited secretion of IL-1 by Mo in response to LPS. This effect, however, did not correlate with the inhibition of plasminogen dependent fibrinolysis. This suggested a degree of sequestration and inaccessibility of membrane bound u-PA of LPS activated Mo to PAI-1. PAI-1, in addition, inhibited mitogen stimulated peripheral blood mononuclear cell (PBMC) proliferation at similar concentration ranges. This effect was abrogated by the addition of specific antisera to PAI-1. PAI-1 may be released as part of an acute phase response. In addition to influencing fibrinolysis, PAI-1 may constitute a negative feedback pathway on Mo IL-1 release and subsequent immune activation in vivo.
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PMID:Monocyte-macrophage release of IL-1 is inhibited by type-1 plasminogen activator inhibitors. 196 70

Immunogold EM was employed to compare the distribution of type 1 plasminogen activator inhibitor (PAI-1) on the surface of agonist-activated human umbilical vein endothelial cells (HUVECs) with that of control, unactivated cells. As previously observed, (Schleef, R.R., T.J. Podor, E. Dunne, J. Mimuro, and D.J. Loskutoff. J. Cell Biol. 110:155-163), analysis of cross-sections of nonpermeabilized control HUVEC monolayers stained first with affinity-purified rabbit antibodies to PAI-1 and then with gold-conjugated goat anti-rabbit IgG, revealed the presence of relatively few gold particles (less than 1-2% of the total) on the apical cell surface. The majority of gold particles were detected primarily in the extracellular matrix between the culture substratum and the cell membrane. In contrast, treatment of HUVECs with tumor necrosis factor alpha (TNF alpha; 200 U/ml, 24 h) or with lipopolysaccharide (LPS; 10 micrograms/ml, 24 h) resulted in an increased staining of PAI-1 not only in the extracellular matrix, but also on the apical cell surface (10-fold increase). Immunoabsorption of the rabbit anti-PAI-1 with purified PAI-1, or treatment of HUVECs with tissue-type plasminogen activator (2.5 micrograms/ml, 2 h, 4 degrees C) reduced the amount of staining both on the apical surface and in the extracellular matrix of agonist-activated HUVECs by 80-95%. The topographical location of PAI-1 on the cell surface was examined further by coupling immunogold staining with high resolution surface replication. Transmission EM of surface replicas from TNF alpha- or LPS-activated HUVECs revealed a general increase in PAI-1 staining both on planar regions and within indentations of the apical cell surface. Nonactivated HUVECs revealed PAI-1-specific immunogold particles only in areas of exposed extracellular matrix between the cells and occasionally at regions of cell-cell contacts. Analysis of activated bovine aortic endothelial cells by immuno-electron microscopy, immunologic assays, and flow cytometry revealed similar increases in surface PAI-1. These increases in surface PAI-1 could be detected by 3 h and continued over a 24-h period. The expression of PAI-1 on the luminal surface of endothelial cells during immune or inflammatory reactions could reduce endothelial fibrinolytic activity, thus, promoting the localized, pathologic formation of intravascular thrombi.
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PMID:Immunoelectron microscopic localization of type 1 plasminogen activator inhibitor on the surface of activated endothelial cells. 204 19

Seven healthy male volunteers were subjected to exercise of short (STR; 1.7 km), middle (MTR; 4.8 km) and long (LTR; 10.5 km) term runs at a speed close to maximal capacity. Blood samples were drawn before, immediately after exercise and at intervals over the next 10 h. FVIIIR:Ag (von Willebrand factor) rose 2.2-3.2 fold and persisted at higher levels than baseline during the observation time. A spontaneous drop in FVII (p less than 0.03) was found immediately after STR (13.5 +/- 2.5%) and LTR (18.3 +/- 2.4%), whereas only a minor decrease (7.5 +/- 6.5%) occurred in MTR. The procoagulant activity of monocytes isolated from whole blood exposed to LPS showed a striking enhancement in STR and MTR. An immediate enhancement in fibrinolytic activity was found in all groups (p less than 0.03) assessed by increased plasma levels of t-PA and shortened whole blood clot lysis time (WBCLT). The transient shortening of WBCLT was succeeded by a tendency to prolongation of the lysis time. A 45-year old male differed markedly from the others by demonstrating an extreme and consistent prolongation of WBCLT. Thus, it has been speculated that strenuous exercise possibly makes a subject more susceptible to a thrombotic event.
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PMID:Formation and persistence of procoagulant and fibrinolytic activities in circulation after strenuous physical exercise. 209 90

In vitro effect of cisplatin and other biological response modifiers has been studied. It is observed that in vitro treatment of macrophage monolayers with cisplatin, rIFN Y, LPS or MDP either alone or in combination showed significantly increased activity of lysozyme, plasminogen activator and decreased activity of 5' nucleotidase. Priming of macrophages with rIFN Y had a significant effect in enhancing the activity of lysozyme and plasminogen activator when subsequently treated with cisplatin, MDP or LPS.
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PMID:Effect of cisplatin and other biological response modifiers on the activity of lysozyme, plasminogen activator and 5' nucleotidase by murine macrophages in vitro. 212 98

Cells of the monocyte/macrophage lineage are known to produce urokinase type plasminogen activator (u-PA) and are active participants in the inflammatory response. Modulation of cellular u-PA production, for instance in response to LPS, may have an important impact on the evolution of inflammatory lesions. A definitive picture of how monocyte u-PA production and activity are regulated by LPS is lacking. We addressed this issue directly by measuring u-PA Ag and activity in mononuclear cell cultures. By using a competition ELISA to quantitate u-PA Ag, we found that LPS-stimulated mononuclear cells in culture increased u-PA production in a dose-dependent manner and that all the u-PA detected was attributable to the monocytes therein. Increasing amounts of u-PA were secreted into the medium, bound to the cell surface, and found intracellularly. Although the absolute amounts of u-PA varied from donor to donor, the increases seen with LPS stimulation were a consistent and statistically significant finding. Only the cell-surface-bound u-PA was fibrinolytically active, however, with this activity increasing upon LPS stimulation. All monocyte cell-surface-associated fibrinolytic activity was attributed to u-PA, as shown by plasminogen dependence, neutralization by antibodies to u-PA, and identification of fibrinolytically active molecules eluted from the cell surface. The surface bound u-PA was not inhibited by its physiologic inhibitors, PAI-1 or PAI-2, whereas free u-PA was. Hence LPS stimulation results in monocytes exhibiting increased cell-surface-associated u-PA Ag and fibrinolytic activity, in spite of concomitant high levels of plasminogen activator inhibitor type 2 production. This surface-bound enzymatic activity may influence the ability of monocytes to migrate in and interact with an inflammatory microenvironment.
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PMID:Lipopolysaccharide-induced modulation of human monocyte urokinase production and activity. 225 14

Mononuclear phagocytes regulate the generation of plasmin by secreting urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-2 (PAI-2). We investigated the production of plasminogen activator (PA) and PA inhibitor by the human monocytic leukemia cell line, THP-1. Similar to U937 monoblast-like cells and peripheral blood monocytes (PBM), THP-1 cells produce a PA that is specifically neutralized by anti-uPA antibody and comigrates with human high molecular mass uPA (54 kDa) on casein-plasminogen zymogaphy. PA activity could be dissociated from intact THP-1 cells by brief treatment with a weak acid-glycine buffer, indicating that the uPA is secreted and bound to receptors on the plasma membrane. Regulation of uPA proceeds normally in THP-1 cells, with cell-associated PA activity increasing from 77 +/- 20 to 163 +/- 26 and 325 +/- 30 mPU/10(6) cells in response to PMA and LPS, respectively; parallel increases in steady state levels of uPA mRNA were observed. In contrast to normal expression of uPA activity, functional PAI-2 could not be demonstrated in either the conditioned media or cell lysates of THP-1 under basal or stimulated conditions. Both U937 and PBM secrete low levels of PA inhibitor activity that increase substantially in response to stimulation with PMA and LPS. Immunoreactive PAI-2, measured by ELISA, was undetectable in THP-1 lysates or conditioned medium, but was consistently present in U937 and PBM, paralleling the presence of PA inhibitor activity. THP-1 cells express low levels of an abnormally sized mRNA for PAI-2 and demonstrate a regulatory defect whereby steady state levels of PAI-2 mRNA are markedly reduced upon stimulation with PMA or LPS. By contrast, U937 and PBM respond to identical stimulation with increases in PAI-2 mRNA. We conclude that THP-1 cells express a structurally abnormal species of PAI-2 mRNA, with complete loss of inhibitory activity as well as altered function of PMA- and LPS-responsive regulatory elements.
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PMID:The THP-1 cell line is a urokinase-secreting mononuclear phagocyte with a novel defect in the production of plasminogen activator inhibitor-2. 230 45

The plasminogen activator inhibitor (PAI-1) from endothelial cells is a potentially important regulator of plasminogen activator activity. Cultured human endothelial cells increase their PAI-1 production upon stimulation with LPS and TNF, agents that are known to cause an increase in PAI-1 levels in vivo. We isolated a PAI-1 cDNA probe, and by RNA hybridization analysis studied the regulation of PAI-1 mRNA synthesis in human endothelial artery cells. Freshly isolated endothelial cells do not contain detectable amounts of PAI-1 mRNA, but after adherence and incubation for 18 h in growth medium produce considerable amounts of PAI-1 activity and contain PAI-1 mRNA levels comparable to those found in subcultured cells. When subcultured endothelial cells are incubated for 6 h with LPS or TNF, both species of PAI-1 mRNA increase 10 to 20 fold, while PAI-1 activity in the growth medium increases only 1.5 to 2 fold. Stimulation of endothelial cells in the presence of cycloheximide (CHX) results in superinduction of mainly the 3.0 kb PAI-1 mRNA. The 3' end of this mRNA contains a 60 bp AT-rich sequence, that resembles 3' sequences present in a number of other genes superinducible with CHX.
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PMID:Regulation of plasminogen activator inhibitor-1 mRNA in human endothelial cells. 246 Sep 66

We characterized immunologic induction of monocyte plasminogen activator (PA) to determine whether assay for PA induction reliably detected cell-mediated immunity (CMI). Mononuclear leukocytes (MNL) were incubated in teflon-lined culture tubes for 1-4 days in the presence or absence of phytohemagglutinin-P (PHA), concanavalin A (Con A) or Candida antigen. PA activity of the monocytes in those suspensions was then measured using a micro fibrin plate assay. Monocytes in stimulated MNL had more PA activity than monocytes in unstimulated MNL. Maximal differences between stimulated and unstimulated cells were seen after 2 days of culture. Dose-response studies demonstrated that PA induction occurred at submitogenic concentrations of stimuli. Peak induction was seen using suboptimally mitogenic concentrations of PHA, Con A and Candida antigen. PA induction in response to Candida stimulation corresponded with skin test results. More than 90% of healthy adults tested had positive assays to all stimuli. LPS, in picogram concentrations, induced PA activity in the absence of lymphocytes, but such induction was prevented by polymyxin B. Supernates from activated MNL also induced PA in purified monocytes. This indirect assay of PA induction was less sensitive than direct assay of the MNL. A standard indirect assay for leukocyte inhibitory factor (LIF) was also less sensitive than the direct PA induction assay. The direct PA induction assay is sensitive and convenient and requires small volumes of blood. It may prove valuable in in vitro analysis of cell-mediated immunity in health and disease.
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PMID:Immune induction of human monocyte plasminogen activator. Characteristics of an assay for cell-mediated immunity. 298 56

Human IL-1, recombinant murine IL-1 and E. coli LPS were found to be potent inducers of plasminogen activator (PA)-inhibitor activity, both in vivo, in rats, as well as in cultured human endothelial cells. In vivo, LPS rapidly and dose-dependently (0.01-1,000 micrograms/kg) increased plasma PA-inhibitor activity. Infusion of IL-1 into rats resulted in a small but significant increase in PA-inhibitor activity in rat plasma. Likewise, in cultured human umbilical vein endothelial cells, LPS and IL-1 induced increased synthesis of PA-inhibitor. We suggest that the induced rat plasma inhibitor might be of endothelial origin.
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PMID:Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. 308 1


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