ABSTRACT
BACKGROUND: Protease-activated receptors (PARs) are G-protein-coupled receptors that function in hemostasis and thrombosis, as well as in the inflammatory and proliferative responses triggered by tissue injury. We have previously shown that PAR1 or PAR2 occupancy by specific PAR-agonist peptides (PAR-APs) induces tissue factor (TF) expression in human umbilical vein endothelial cells (HUVECs), where TF regulation by PAR1 (but not by PAR2) requires intact endothelial caveolin-enriched membrane microdomains in which PAR1 and caveolin-1 associate. OBJECTIVES: The aim of this study was to determine the effects of cholesterol-lowering agents (statins) and cholesterol-loading lipoprotein on PAR1-AP-mediated and PAR2-AP-mediated TF induction in HUVECs. RESULTS: Statins completely prevented TF induction by PAR-APs in an isoprenoid-independent manner, induced the delocalization of PAR1 from caveolin-enriched membrane microdomains without affecting PAR1 mRNA, and decreased PAR2 mRNA and protein levels. Statins also prevented PAR-AP-mediated extracellular signal-related kinase 1/2 activation, which is crucial for TF induction. The redistribution of PAR1 is accompanied by the relocation of the membrane microdomain-associated G-protein α, caveolin-1, and Src, which we previously showed to play a key role in signal transduction and TF induction. Conversely, cholesterol loading potently amplified PAR1-AP-induced TF, probably as a result of the increased abundance of PAR1 and the Src and G-protein α signaling molecules in the caveolin-1-enriched fraction, without affecting PAR1 mRNA. CONCLUSIONS: As PARs have important functions in hemostasis, cancer, thrombosis, and inflammatory processes, our findings that statins prevent TF induction by PAR-APs altering the membrane localization of PAR1 and the expression of PAR2 suggest that they may provide health benefits other than reducing atherosclerosis.
Subject(s)
Fatty Acids, Monounsaturated/pharmacology , Fluorobenzenes/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Indoles/pharmacology , Pyrimidines/pharmacology , Receptor, PAR-1/drug effects , Receptor, PAR-2/drug effects , Sulfonamides/pharmacology , Thromboplastin/metabolism , Caveolin 1/metabolism , Cells, Cultured , Cholesterol/metabolism , Enzyme Activation , Fluvastatin , GTP-Binding Protein alpha Subunits/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Membrane Microdomains/drug effects , Membrane Microdomains/metabolism , Mevalonic Acid/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Protein Transport , RNA, Messenger/metabolism , Receptor, PAR-1/genetics , Receptor, PAR-1/metabolism , Receptor, PAR-2/genetics , Receptor, PAR-2/metabolism , Rosuvastatin Calcium , Signal Transduction/drug effects , Terpenes/metabolism , Up-Regulation , src-Family Kinases/metabolismABSTRACT
Organic matter balances of an ECF kraft mill fiberline were studied in three different operational conditions of the oxygen delignification stage by implementing mill measurements, collecting routine mill data and combining them in a modified PROCELL steady state model. Dissolved volatile solids was the basic measurement for organic matter in liquid streams. Normal operation of the O2D0E(O)D1E(OP)D2 fiberline was described successfully. It was also possible to describe exceptional operating situations in the oxygen delignification stage and their effects on other parts of the production process reasonably well in order to focus studies on aspects requiring further attention. The existence of organic matter lost through complete degradation and volatile organic compounds in unit processes as well as its sensitivity to yield and operational situations is shown. The different perspectives of pulp production and wastewater treatment can be brought closer to each other using the approach in this study. The variation in the fractions discharged to wastewater treatment, although a relatively small share of the overall organic matter balance, will continue to become more important also for pulp production when effluent streams are increasingly turned back to the production line through further closure. Studies like the one presented here, can contribute to the evaluation of this development.
Subject(s)
Industrial Waste , Lignin/isolation & purification , Models, Theoretical , Waste Disposal, Fluid/methods , Organic Chemicals/analysis , Organic Chemicals/metabolism , Paper , Solubility , VolatilizationABSTRACT
Efficiency improvement in a pulp mill includes minimisation of environmental discharges simultaneously with the development of pulp quality and production economy. Material balances in production processes, including fate of sidestreams, are key in proceeding these matters. Different approaches of determining the material balances increase understanding of process behaviour. We have focused on measuring sidestream (carryovers, washing water, filtrate) dissolved organic matter (DOM) in fibreline unit process blocks of softwood ECF bleached kraft production. The DOM was analysed by traditional wastewater methods (volatile solids, organic carbon, chemical oxygen demand). The measured data was combined with primarily simulated water balances and routine operational mill data in a simulation model. From this balance, yield estimate included, lost organic matter through complete degradation (CD) and volatile organic compounds (VOC) can be calculated throughout the fibreline. The sensitivity of this considerable amount (23-35 kgDVS/adt in total) to various factors is discussed in this paper.
