[en] ABSTRACT: BACKGROUND: Increase in tissue factor (TF) and loss in thrombomodulin (TM) antigen levels has been described in various inflammatory disorders. The functional consequences of such changes in antigen concentrations in the coagulation balance are, however, not known. This study was designed to assess the consequences of inflammation-driven organ specific functional properties of the procoagulant response. METHODS: Tissue specific procoagulant activity was assessed by adding tissue homogenate to normal human pool plasma and recording of the thrombin generation curve. The new technique was subsequently applied on two inflammation driven animal models: 1) mouse lipopolysaccharide (LPS) induced endotoxemia and 2) spontaneously hypertensive rats exposed to environmental air pollution (particulate matter (PM). RESULTS: Addition of lung tissue from untreated animals to human plasma suppressed the endogenous thrombin potential (ETP) (175 +/- 61 vs. 1437 +/- 112 nM.min for control). This inhibitory effect was due to TM, because a) it was absent in protein C deficient plasma and b) lungs from TMpro/pro mice allowed full thrombin generation (ETP: 1686 +/- 209 nM.min). The inhibitory effect of TM was lost after LPS administration to mice, which induced TF activity in lungs of C57Bl/6 mice as well as increased the ETP (941 +/- 523 vs. 194 +/- 159 nM.min for control). Another pro-inflammatory stimulus, PM dose-dependently increased TF in the lungs of spontaneously hypertensive rats at 4 and 48 hours after PM exposure. The ETP increased up to 48 hours at the highest concentration of PM (1441 +/- 289 nM.min vs. saline: 164 +/- 64 nM.min, p < 0.0001), suggesting a concentration- and time dependent reduction in TM activity. CONCLUSION: Inflammation associated procoagulant effects in tissues are dependent on variations in activity of the TF-TM balance. The application of these novel organ specific functional assays is a useful tool to monitor inflammation-driven shifts in the coagulation balance within animal or human tissues.
Poll van der T Levi M Hack CE et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees J Exp Med 1994, 179:1253-1259 2191443 8145042 10.1084/ jem.179.4.1253
Falati S Liu Q Gross P et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin J Exp Med 2003, 197:1585-1598 2193915 12782720 10.1084/jem.20021868
Levi M Poll van der T Two-way interactions between inflammation and coagulation Trends Cardiovasc Med 2005, 15:254-259 10.1016/ j.tcm.2005.07.004 16226680
Herbert JM Savi P Laplace MC et al. Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells Thromb Res 1993, 71:487-493 10.1016/0049-3848(93)90122-5 8134908
Nan B Lin P Lumsden AB et al. Effects of TNF-alpha and curcumin on the expression of thrombomodulin and endothelial protein C receptor in human endothelial cells Thromb Res 2005, 115:417-426 10.1016/ j.thromres.2004.10.010 15733976
Conway EM Rosenberg RD Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells Mol Cell Biol 1988, 8:5588-5592 365667 2854203
Faust SN Levin M Harrison OB et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis N Engl J Med 2001, 345:408-416 10.1056/NEJM200108093450603 11496851
Hatakeyama K Asada Y Marutsuka K et al. Localization and activity of tissue factor in human aortic atherosclerotic lesions Atherosclerosis 1997, 133:213-219 10.1016/S0021-9150(97)00132-9 9298681
Yoshii Y Okada Y Sasaki S et al. Expression of thrombomodulin in human aortic smooth muscle cells with special reference to atherosclerotic lesion types and age differences Med Electron Microsc 2003, 36:165-172 10.1007/s00795-003-0212-5 14505060
Rao LV Tissue factor as a tumor procoagulant Cancer Metastasis Rev 1992, 11:249-266 10.1007/BF01307181 1423817
Ogawa H Yonezawa S Maruyama I et al. Expression of thrombomodulin in squamous cell carcinoma of the lung: Its relationship to lymph node metastasis and prognosis of the patients Cancer Lett 2000, 149:95-103 10.1016/S0304-3835(99)00348-1 10737713
Hanly AM Hayanga A Winter DC et al. Thrombomodulin: Tumour biology and prognostic implications Eur J Surg Oncol 2005, 31:217-220 10.1016/ j.ejso.2004.11.017 15780553
Anderson HR Ponce de Leon A Bland JM et al. Air pollution and daily mortality in London: 1987-92 Bmj 1996, 312:665-669 2350512 8597732
Dockery DW Pope CA 3rd Xu X et al. An association between air pollution and mortality in six U.S. cities N Engl J Med 1993, 329:1753-1759 10.1056/NEJM199312093292401 8179653
Pope CA 3rd Burnett RT Thun MJ et al. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution Jama 2002, 287:1132-1141 10.1001/jama.287.9.1132 11879110
Peters A Dockery DW Muller JE et al. Increased particulate air pollution and the triggering of myocardial infarction Circulation 2001, 103:2810-2815 11401937
Miller KA Siscovick DS Sheppard L et al. Long-term exposure to air pollution and incidence of cardiovascular events in women N Engl J Med 2007, 356:447-458 10.1056/NEJMoa054409 17267905
Weiler H Lindner V Kerlin B et al. Characterization of a mouse model for thrombomodulin deficiency Arterioscler Thromb Vasc Biol 2001, 21:1531-1537 10.1161/hq0901.094496 11557684
Sommeijer DW van Oerle R Reitsma PH et al. Analysis of blood coagulation in mice: Pre-analytical conditions and evaluation of a home-made assay for thrombin-antithrombin complexes Thromb J 2005, 3:12 1215525 16115315 10.1186/1477-9560-3-12
Gerlofs-Nijland ME Boere AJ Leseman DL et al. Effects of particulate matter on the pulmonary and vascular system: Time course in spontaneously hypertensive rats Part Fibre Toxicol 2005, 2:2 1079943 15813961 10.1186/1743-8977-2-2
Demokritou P Gupta T Ferguson S et al. Development and laboratory performance evaluation of a personal cascade impactor J Air Waste Manag Assoc 2002, 52:1230-1237 12418733
Vincent R Bjarnason SG Adamson IY et al. Acute pulmonary toxicity of urban particulate matter and ozone Am J Pathol 1997, 151:1563-1570 1858352 9403707
Vincent R Goegan P Johnson G et al. Regulation of promoter-CAT stress genes in HepG2 cells by suspensions of particles from ambient air Fundam Appl Toxicol 1997, 39:18-32 10.1006/faat.1997.2336 9325024
Chomczynski P Rymaszewski M Alkaline polyethylene glycol-based method for direct PCR from bacteria, eukaryotic tissue samples, and whole blood Biotechniques 2006, 40:454, 456, 458 16629392
Cosemans JM Kuijpers MJ Lecut C et al. Contribution of platelet glycoprotein VI to the thrombogenic effect of collagens in fibrous atherosclerotic lesions Atherosclerosis 2005, 181:19-27 10.1016/ j.atherosclerosis.2004.12.037 15939050
Hemker HC Giesen P AlDieri R et al. The calibrated automated thrombogram (CAT): A universal routine test for hyper- and hypocoagulability Pathophysiol Haemost Thromb 2002, 32:249-253 10.1159/000073575 13679651
Luther T Dittert DD Kotzsch M et al. Functional implications of tissue factor localization to cell-cell contacts in myocardium J Pathol 2000, 192:121-130 10.1002/ 1096-9896(2000)9999:9999<::AID-PATH667>3.0.CO;2-I 10951409
Kooter I Pennings J Opperhuizen A et al. Gene expression pattern in spontaneously hypertensive rats exposed to urban particulate matter (EHC-93) Inhal Toxicol 2005, 17:53-65 10.1080/08958370590885717 15764483
Esmon CT The interactions between inflammation and coagulation Br J Haematol 2005, 131:417-430 10.1111/j.1365-2141.2005.05753.x 16281932
Levi M Poll van der T Buller HR Bidirectional relation between inflammation and coagulation Circulation 2004, 109:2698-2704 10.1161/ 01.CIR.0000131660.51520.9A 15184294
Moore KL Esmon CT Esmon NL Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture Blood 1989, 73:159-165 2535943
Faust SN Heyderman RS Levin M Coagulation in severe sepsis: A central role for thrombomodulin and activated protein C Crit Care Med 2001, 29:S62-67 10.1097/00003246-200107001-00022 11445736
Terada Y Eguchi Y Nosaka S et al. Capillary endothelial thrombomodulin expression and fibrin deposition in rats with continuous and bolus lipopolysaccharide administration Lab Invest 2003, 83:1165-1173 10.1097/ 01.LAB.0000080606.96797.A5 12920245
Fujii T Hayashi S Hogg JC et al. Particulate matter induces cytokine expression in human bronchial epithelial cells Am J Respir Cell Mol Biol 2001, 25:265-271 11588002
Coughlin SR Camerer E PARticipation in inflammation J Clin Invest 2003, 111:25-27 151847 12511583
Chalmers CJ Balmanno K Hadfield K et al. Thrombin inhibits Bim (Bcl-2-interacting mediator of cell death) expression and prevents serum-withdrawal-induced apoptosis via protease-activated receptor 1 Biochem J 2003, 375:99-109 1223666 12844349 10.1042/BJ20030346
Tsopanoglou NE Maragoudakis ME On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors J Biol Chem 1999, 274:23969-23976 10.1074/jbc.274.34.23969 10446165