Thrombomodulin is present in human plasma and urine.

Ishii, Hidemi; Majerus, Philip W.

doi:10.1172/jci112225

Cited by 294 publications

(166 citation statements)

References 14 publications

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“…Previous reports have described the interactions between immune mucosal cells and ECs that contribute to intestinal homeostasis and intestinal epithelial permeability (19), indicating the likely presence of cross-talk between ECs and other cells expressing TM. However, a TM-soluble form, derived from the endothelial membrane, is released in plasma, but whether this form is functional is unknown (20).…”

Section: Discussionmentioning

confidence: 99%

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC −/− /PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.

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Section: Discussionmentioning

confidence: 99%

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Soluble forms of TM derived from the extracellular domain of the molecule have been found in the plasma and urine of healthy subjects, suggesting that it is cleaved under physiological conditions. 5,41 The increase in plasma TM fragments in patients with various diseases suggests that TM release from endothelial cells is accelerated by proteolytic activity generated on the surface of the endothelium. 5 The proteases responsible for TM shedding are still unknown, although neutrophil-derived enzymes-including elastase, proteinase-3, and cathepsin G-have been implicated.…”

Section: Discussionmentioning

confidence: 99%

“…43 Several soluble TM subspecies that maintain the structure of the fourth to sixth EGF-like repeats have protein C-activating cofactor activity, although the physiological significance is obscure. 41 Whether these natural soluble TM subspecies mimic the mitogenic or angiogenic properties noted with recombinant TMD23 remains to be studied. In the present study, we demonstrated that TMD23 can promote angiogenesis in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Human Thrombomodulin Domain as a Novel Angiogenic Factor

Shi

Chang

et al. 2005

Circulation

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Background-Thrombomodulin is an anticoagulant, endothelial-cell-membrane glycoprotein. A recombinant thrombomodulin domain containing 6 epidermal growth factor-like structures exhibits mitogenic activity. This study explored the novel angiogenic effects of the recombinant domain using in vitro and in vivo models. Methods and Results-Human recombinant thrombomodulin containing 6 epidermal growth factor-like structures (TMD2) and TMD2 plus a serine and threonine-rich domain (TMD23) were prepared using the Pichia pastoris expression system. Combined with purified TMD2 or TMD23, thrombin effectively activated protein C. TMD23 had higher activity than TMD2 in stimulating DNA synthesis in cultured human umbilical vein endothelial cells. Additionally, TMD23 stimulated chemotactic motility and capillarylike tube formation in human umbilical vein endothelial cells, an effect mediated through phosphorylation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase and the phosphatidylinositol-3 kinase/Akt/endothelial nitric oxide synthase pathway. TMD23 also stimulated endothelial cell expression of matrix metalloproteinases and plasminogen activators, which mediated extracellular proteolysis, leading to endothelial cell invasion and migration during angiogenesis. Furthermore, TMD23-containing implants in rat cornea induced ingrowth of new blood vessels from the limbus. With the murine angiogenesis assay, TMD23 not only induced neovascularization coinjected with Matrigel and heparin but also enhanced angiogenesis in Matrigel containing melanoma A2058 cells in nude mice. Conclusions-The

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“…TM is also present as soluble heterogeneous fragments in circulating plasma and increased plasma levels of this soluble TM (s-TM) are considered to be associated with injury to endothelial cells. 10) In patients with coronary artery disease, elevated s-TM levels were found to be related to recurrent coronary events, 11) although high s-TM concentrations have been reported to be associated with a reduced risk of coronary heart disease.…”

mentioning

confidence: 99%

Plasma Levels of Soluble Thrombomodulin, C-reactive Protein, and Serum Amyloid A Protein in the Atherosclerotic Coronary Circulation

et al. 2003

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SUMMARYPlasma levels of C-reactive protein (CRP) and serum amyloid A protein (SAA), inflammatory markers, and soluble thrombomodulin (s-TM), a marker of endothelial damage, are thought to be related to coronary artery disease. However, the relationship between these inflammatory markers and endothelial injury in atherosclerotic coronary arteries is still unclear.Fifty-five patients who underwent coronary angiography were classified into 3 groups according to the severity of left coronary arterial atherosclerosis evaluated by the Gensini score (GS; normal: score = 0, n = 15; mild: 0 < score < 15, n = 29; severe: score ≥ 15, n = 11). Blood samples were obtained from the aortic root (Ao) and coronary sinus (CS) and plasma CRP and SAA levels were measured by latex turbidimetric immunoassays, and s-TM levels were determined by an enzyme-linked immunosorbent assay. The difference between marker concentrations in the Ao and CS of the coronary circulation was expressed as the coronary sino-arterial (CS-Ao) difference.The CS-Ao differences of s-TM and SAA were significantly higher in patients with severe atherosclerosis than in normal patients (P < 0.01), and showed weak but significant positive correlations with the GS (r = 0.34, P < 0.01 and r = 0.33, P < 0.05, respectively). The CS-Ao differences in CRP did not differ among the three groups, and did not correlate with the GS.The results of our study reveal a possible relationship between endothelial cell injury and inflammation in atherosclerotic coronary arteries. (Jpn Heart J 2003; 44: 601-612)

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Thrombomodulin is present in human plasma and urine.

Cited by 294 publications

References 14 publications

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Evidence of Human Thrombomodulin Domain as a Novel Angiogenic Factor

Plasma Levels of Soluble Thrombomodulin, C-reactive Protein, and Serum Amyloid A Protein in the Atherosclerotic Coronary Circulation

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