Disease relevance of Thbd

• Inactivation of the TM gene in mice results in embryonic lethality without thrombosis, suggesting that structures of TM not recognized to be involved in coagulation might be critical for normal fetal development [1].
• These data suggest that a TM mutation that impairs APC generation results in uncontrolled lung inflammation during tuberculosis [2].
• To investigate the role of TM in the coagulant and inflammatory response in the lung during tuberculosis, mice with a mutation in the TM gene (Thbd), which results in a minimal capacity for APC generation (TMpro/pro mice), were intranasally infected with live virulent Mycobacterium tuberculosis [2].
• The structure and function of mouse thrombomodulin. Phorbol myristate acetate stimulates degradation and synthesis of thrombomodulin without affecting mRNA levels in hemangioma cells [3].
• Vascular immunotargeting of glucose oxidase to the endothelial antigens induces distinct forms of oxidant acute lung injury: targeting to thrombomodulin, but not to PECAM-1, causes pulmonary thrombosis and neutrophil transmigration [4].

High impact information on Thbd

• The thrombomodulin-protein C system is essential for the maintenance of pregnancy [5].
• Disruption of the mouse gene encoding the blood coagulation inhibitor thrombomodulin (Thbd) leads to embryonic lethality caused by an unknown defect in the placenta [5].
• These findings show a new function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta [5].
• The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways [6].
• These data suggest that TM has antiinflammatory properties in addition to its role in coagulation and fibrinolysis [6].

Chemical compound and disease context of Thbd

• Transcription of thrombomodulin mRNA in mouse hemangioma cells is increased by cycloheximide and thrombin [7].
• We reported that a cell surface thrombin receptor, thrombomodulin (TM), was regulated by cyclic AMP in fibroblasts and in parietal endoderm-like cells derived from F9 embryonal carcinoma cells [8].
• Activation of thrombomodulin-encoding gene (TM) transcription in murine teratocarcinoma F9 cells occurs during differentiation in response to retinoic acid (RA) and dibutyryl cAMP (dbcAMP) [9].
• A high level of endogenous p15E-related peptide expression in spleen cells of mice with hemolytic anemia rendered by phenylhydrazine (PHZ) treatment was observed, detected by hyperimmune rabbit antisera against amino acid sequence which compose the immunosuppressive domain (ISD) of exogenous viral transmembrane (TM) p15E protein [10].

Biological context of Thbd

• We show that the abortion of thrombomodulin-deficient embryos is caused by tissue factor-initiated activation of the blood coagulation cascade at the feto-maternal interface [5].
• Cross-breeding of F1 TMwt/cyt mice (1 wild-type and 1 mutant allele) resulted in more than 300 healthy offspring with a normal Mendelian inheritance pattern of 25.7% TMwt/wt, 46.6% TMwt/cyt, and 27.7% TMcyt/cyt mice, indicating that the tail of TM is not necessary for normal fetal development [1].
• These findings demonstrate a dual role of TM in development, and that a loss of TM function disrupts mouse embryogenesis at two different stages [11].
• The deduced amino acid sequence of mouse thrombomodulin is similar to those determined for human and bovine thrombomodulin [3].
• Our studies suggested that altered shear stress induced significant TM gene expression changes during the arterial remodeling process [12].

Anatomical context of Thbd

• Here, we show that reconstitution of TM expression in extraembryonic tissue by aggregation of tetraploid wild-type embryos with TM-null embryonic stem cells rescues TM-null embryos from early lethality [11].
• These two functions of TM are exerted in two distinct tissues: expression of TM in non-endothelial extraembryonic tissues is required for proper function of the early placenta, while the absence of TM from embryonic blood vessel endothelium causes lethal consumptive coagulopathy [11].
• Mouse monoclonal anti-human thrombomodulin antibodies bind to and activate endothelial cells through NF-kappaB activation in vitro [13].
• Remodeling of carotid arteries is associated with increased expression of thrombomodulin in a mouse transverse aortic constriction model [12].
• 5. An overall retardation in growth and development of TM-/- embryos is first evident on embryonic day 8.5 (8-12 somite pairs) [14].

Associations of Thbd with chemical compounds

• Thrombomodulin (TM) is a widely expressed glycoprotein receptor that plays a physiologically important role in maintaining normal hemostatic balance postnatally [1].
• Thrombomodulin mutant mice with a strongly reduced capacity to generate activated protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide [15].
• Thrombomodulin transcription in response to cycloheximide treatment, as determined by nuclear run-on analysis, was 3.9 +/- 1.3 (mean +/- SD) times that found in untreated cells [7].
• We propose that there are at least two separate genomic DNA regions that regulate cyclic AMP-dependent TM gene expression and that their functions are cell type dependent [8].
• Given the importance of thrombomodulin/thrombin interaction in regulating protein C activity, decreases in thrombomodulin may contribute to activation of the coagulation and inflammatory cascades and development of lung injury with hyperoxia [16].

Regulatory relationships of Thbd

• A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis [2].
• These initial changes take place at a time when TM is normally expressed in the parietal yolk sac [14].
• In this context, we newly found that an endothelial anticoagulant thrombomodulin was expressed in the normal islet beta cells and insulinoma, but not of other islet components or noninsulinoma islet cell tumors [17].

Other interactions of Thbd

• Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function [18].
• To test its protective effect, we employed a murine model of oxidative lung injury induced by glucose oxidase coupled with thrombomodulin antibody (anti-TM/GOX) [19].
• Tissue factor expression was up-regulated as well, and thrombomodulin gene expression was down-regulated [20].
• The removal of embryonic day 7.5 TM-/- embryos from maternal decidua and their subsequent culture in vitro allow development to proceed to stages not observed in vivo (13-20 somite pairs) with the appearance of normal blood vessels in the visceral yolk sac and embryo [14].
• To examine the functional role of thrombomodulin, especially regarding the clinical characteristics of islet cell tumors, we tested the effect of exogenous thrombomodulin overexpression on cell adhesiveness and proliferation using MIN6 insulinoma cell line [17].

Analytical, diagnostic and therapeutic context of Thbd

• Structure-function analyses of thrombomodulin by gene-targeting in mice: the cytoplasmic domain is not required for normal fetal development [1].
• Cycloheximide, an inhibitor of protein synthesis, increased levels of thrombomodulin mRNA, as measured in an S1 nuclease protection assay, to 2.5-4.0 times control levels [7].
• Thrombin treatment of hemangioma cells also caused an increase in thrombomodulin protein synthesis to 142 +/- 17% (mean +/- SD) of control levels as determined by immunoprecipitation of [32S]methionine-labeled thrombomodulin [7].
• Quantitative Northern blot data coincides with the two-site assay data and demonstrates that the high level of TM expression in lung is not due to preferential binding of the monoclonal antibodies to lung TM but rather to increased production of TM mRNA in the lung relative to other highly vascularized organs [21].
• Using immunohistochemistry, we examined thrombomodulin expression during healing of partial-thickness wounds in human skin and full-thickness wounds in mouse skin [22].

References