Anti-adhesive effects of human soluble thrombomodulin and its domains

Kawamoto, Eiji; Nago, Nodoka; Okamoto, Takayuki; Gaowa, Arong; Masui-Ito, Asami; Sakakura, Yosuke; Akama, Yuichi; Soe, Zay Yar; Prajuabjinda, Onmanee; Darkwah, Samuel; Appiah, Michael G; Myint, Phyoe Kyawe; Obeng, Gideon; Park, Eun Jeong; Imai, Hiroshi; Shimaoka, Motomu

doi:10.1016/j.bbrc.2019.02.041

Cited by 9 publications

(8 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is thought that rsTM suppresses leukocyte adhesion and migration by blocking LPS, HMGB1, and extracellular histones, thereby leading to amelioration of inflammation and organ injury [8,44]. Moreover, we and other groups have shown that rsTM inhibits the adhesion that occurs between leukocytes and endothelial cells by directly blocking integrin-integrin ligand interactions [45][46][47]. Unlike these mechanisms by which rsTM suppresses leukocyte adhesion, the results of the current study provide the first evidence that an rsTM-mediated reduction of endothelial cellular stiffness contributes to the suppression of monocyte adhesion to inflamed endothelial cells.…”

Section: Discussionmentioning

confidence: 93%

Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening

Okamoto

Kawamoto

Usuda

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

Endothelial cellular stiffening has been observed not only in inflamed cultured endothelial cells but also in the endothelium of atherosclerotic regions, which is an underlying cause of monocyte adhesion and accumulation. Although recombinant soluble thrombomodulin (rsTM) has been reported to suppress the inflammatory response of endothelial cells, its role in regulating endothelial cellular stiffness remains unclear. The purpose of this study was to investigate the impact of anticoagulant rsTM on lipopolysaccharide (LPS)-induced endothelial cellular stiffening. We show that LPS increases endothelial cellular stiffness by using atomic force microscopy and that rsTM reduces LPS-induced cellular stiffening not only through the attenuation of actin fiber and focal adhesion formation but also via the improvement of gap junction functionality. Moreover, post-administration of rsTM, after LPS stimulation, attenuated LPS-induced cellular stiffening. We also found that endothelial cells regulate leukocyte adhesion in a substrate- and cellular stiffness-dependent manner. Our result show that LPS-induced cellular stiffening enhances monocytic THP-1 cell line adhesion, whereas rsTM suppresses THP-1 cell adhesion to inflamed endothelial cells by reducing cellular stiffness. Endothelial cells increase cellular stiffness in reaction to inflammation, thereby promoting monocyte adhesion. Treatment of rsTM reduced LPS-induced cellular stiffening and suppressed monocyte adhesion in a cellular stiffness-dependent manner.

show abstract

Section: Discussionmentioning

confidence: 93%

Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening

Okamoto

Kawamoto

Usuda

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, sTM is mainly secreted by vascular endothelial cells, and when endothelial damage occurs, sTM is released into the blood, leading to a dramatic increase in serum sTM. Studies by many researchers have shown that serum sTM level can be used as a marker of vascular endothelial injury, and sTM has been approved in treating septic disseminated intravascular coagulation (15,16). Some researchers have also found that the serum sTM level of patients with sepsis is significantly higher than that of healthy people (17).…”

Section: Discussionmentioning

confidence: 99%

Elevated B-type natriuretic peptide (BNP) and soluble thrombomodulin (sTM) indicates severity and poor prognosis of sepsis

Yue¹,

Deng²,

Yang³

et al. 2021

Ann Palliat Med

View full text Add to dashboard Cite

Background: To study the predictive value of B-type natriuretic peptide (BNP) and soluble thrombomodulin (sTM) in the severity stratification and prognosis evaluation of sepsis. Methods:The clinical data of 137 sepsis patients diagnosed and treated in Sichuan Provincial People's Hospital from May 2018 to November 2020 were retrospectively analyzed. Meanwhile, 121 healthy individuals were selected as the control group. Patients with sepsis were allocated into the mild group, severe group, and shock group according to the severity. According to the 28-day prognosis, the patients were allocated into the death group and survival group. The plasma BNP and serum sTM levels in different groups were compared, and their prognostic value was evaluated.Results: Patients with sepsis had significantly higher levels of BNP and sTM than the healthy control group (P<0.05). The levels of BNP and sTM in the mild group were significantly lower than those in the severe group and shock group, and both BNP and sTM were positively correlated with Acute Physiology and Chronic Health Status (APACHE) II score (r=0.595, 0.516, P<0.05). The levels of BNP and sTM in the death group were significantly higher than those in the survival group (P<0.05). The area under curve (AUC) of BNP combined with sTM was significantly greater than that of BNP or sTM alone for the prognosis of sepsis (P<0.05). When the cut-off value of BNP was 625.68 pg/mL, the sensitivity and specificity were 77.42% and 89.42%, respectively. When the cut-off value of sTM was 10.53 ng/mL, the sensitivity and specificity were 83.87% and 94.34%, respectively.Conclusions: Patients with sepsis have significantly higher serum BNP and sTM levels which are positively correlated with the severity of the disease. Both of the 2 indexes have good prognostic value, and the predictive value is higher when combined.

show abstract

“…Thus, in diseases such as sepsis where inhibition of excessive adhesion of neutrophils and vascular endothelial cells is important for the treatment, TMD123-Fc may be a promising candidate for a therapeutic agent. Indeed, exogenously administered rhsTM inhibits leukocyte and vascular endothelial cell adhesion both in vitro and in vivo [27,28]. Therefore, the inhibitory effect of TMD123-Fc with β1 integrin and fibronectin could be applied as a therapeutic strategy for sepsis.…”

Section: Discussionmentioning

confidence: 99%

The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin

et al. 2021

Self Cite

View full text Add to dashboard Cite

Thrombomodulin is a molecule with anti-coagulant and anti-inflammatory properties. Recently, thrombomodulin was reported to be able to bind extracellular matrix proteins, such as fibronectin and collagen; however, whether thrombomodulin regulates the binding of human breast cancer-derived cell lines to the extracellular matrix remains unknown. To investigate this, we created an extracellular domain of thrombomodulin, TMD123-Fc, or domain deletion TM-Fc proteins (TM domain 12-Fc, TM domain 23-Fc) and examined their bindings to fibronectin in vitro by ELISA. The lectin-like domain of thrombomodulin was found to be essential for the binding of the extracellular domain of thrombomodulin to fibronectin. Using a V-well cell adhesion assay or flow cytometry analysis with fluorescent beads, we found that both TMD123-Fc and TMD12-Fc inhibited the binding between β1 integrin of human breast cancer-derived cell lines and fibronectin. Furthermore, TMD123-Fc and TMD12-Fc inhibited the binding of activated integrins to fibronectin under shear stress in the presence of Ca2+ and Mg2+ but not under strong integrin-activation conditions in the presence of Mg2+ without Ca2+. This suggests that thrombomodulin Fc fusion protein administered exogenously at a relatively early stage of inflammation may be applied to the development of new therapies that inhibit the binding of β1 integrin of breast cancer cell lines to fibronectin.

show abstract

Anti-adhesive effects of human soluble thrombomodulin and its domains

Cited by 9 publications

References 22 publications

Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening

Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening

Elevated B-type natriuretic peptide (BNP) and soluble thrombomodulin (sTM) indicates severity and poor prognosis of sepsis

The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin

Contact Info

Product

Resources

About