1)Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences,Ningxia University, Yinchuan 750021, China; 2)State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
Abstract：Thrombomodulin (TM) is a single-chain transmembrane glycoprotein that mainly exists in vascular endothelial cells, hematopoietic progenitor cells, monocytes and macrophages. TM is mainly composed of five structural regions: the N-terminal lectin-like domain which plays a role in anti-inflammatory, and the six epidermal growth factor-like repeats which function as coagulation and fibrinolysis as well as serine-rich threonine regions and transmembrane domains and cytoplasmic domains. TM exhibits anti-inflammatory and anticoagulant effects by binding to thrombin to activate protein C, and TM-thrombin complex can also activate fibrinolytic inhibitors to suppress fibrinolysis. Previous reports showed that inhibiting epithelial mesenchymal transformation, mitogen-activated protein kinase or activating protein C and fibrinolytic inhibitor are the major mechanisms by which TM exerts anti-tumor properties. In atherosclerosis, TM can prevent atherosclerosis by blocking the activation of thrombin-mediated PAR-1 and inhibiting autophagy and apoptosis of endothelial cells. TM lectin-like domains can also bind to thrombin to inhibit its activity and further inhibit pulmonary thrombosis, fibrosis and inflammation. Moreover, TM protein is also involved in the pathogenesis of diabetic nephropathy, preeclampsia and ischemia-reperfusion injury. At present, TM is only clinically used for the treatment of sepsis and disseminated intravascular coagulation. Its role and therapeutic potential in cardiovascular and cerebrovascular diseases, cancers and other diseases deserve further exploration.
牛小芸, 谢喜秀. 血栓调节蛋白在疾病中的作用[J]. 中国生物化学与分子生物学报, 2021, 37(8): 998-1004.
NIU Xiao-Yun, XIE Xi-Xiu. The Role of Thrombomodulin in Diseases. Chinese Journal of Biochemistry and Molecular Biol, 2021, 37(8): 998-1004.
[1] Huang HC, Shi GY, Jiang SJ, et al. Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain[J]. J Biol Chem, 2003, 278(47): 46750-46759 [2] Pan B, Wang X, Kojima S, et al. The fifth epidermal growth factor like region of thrombomodulin alleviates LPS-induced sepsis through interacting with GPR15[J]. Thromb Haemost, 2017, 117(3): 570-579 [3] Yamashita A, Zhang Y, Sanner MF, et al. C-terminal residues of activated protein C light chain contribute to its anticoagulant and cytoprotective activities[J]. Thromb Haemost, 2020, 18(5): 1027-1038 [4] Loghmani H, Conway EM. Exploring traditional and nontraditional roles for thrombomodulin[J]. Blood 2018, 132(2): 148-158 [5] Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway[J]. Arterioscler Thromb Vasc Biol, 2000, 20(12): 2511-2518 [6] Campbell WD, Lazoura E, Okada N, et al. Inactivation of C3a and C5a Octapeptides by Carboxypeptidase R and Carboxypeptidase N[J]. Microbiol Immunol, 2002, 46(2): 131-134 [7] Murakami A, Nakagawa T, Fukushima C, et al. Relationship between decreased expression of squamous cell carcinoma antigen 2 and E-cadherin in primary cervical cancer lesions and lymph node metastasis[J]. Oncol Rep, 2008, 19(1): 99-104 [8] Zheng N, Huo Z, Zhang B, et al. Thrombomodulin reduces tumorigenic and metastatic potential of lung cancer cells by up-regulation of E-cadherin and down-regulation of N-cadherin expression[J]. Biochem Biophys Res Commun, 2016, 476(4): 252-259 [9] Tai C-J, Cheng C--W, Su H-Y, et al. Thrombomodulin mediates the migration of cervical cancer cells through the regulation of epithelial–mesenchymal transition biomarkers[J]. Tumour Biol, 2014,35(1): 47- 54 [10] Yang Y, Cheng BJ, Lu S. Thrombomodulin regulates doxorubicin sensitivity through epithelial- mesenchymal transition in non-small cell lung cancer[J]. Eur Rev Med Pharmacol Sci, 2017, 21(1): 95-101 [11] Chang YJ, Cheng YW, Lin RK, et al. Thrombomodulin influences the survival of patients with non-metastatic colorectal cancer through epithelial-to-mesenchymal transition (EMT)[J]. PLoS One, 2016, 11(8): e0160550 [12] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition[J]. Nat Rev Mol Cell Biol, 2014, 15(3): 178-196 [13] Giri H, Cai X, Panicker SR, et al. Thrombomodulin regulation of mitogen-activated protein kinases[J]. Int J Mol Sci, 2019, 20(8): 1851 [14] de Oliverira Ada S, Yang L, Echvarria-Lima J, et al. Thrombomodulin modulates cell migration in human melanoma cell lines[J]. Melanoma Res, 2014, 24(1): 11-19 [15] Shirai Y, Uwagawa T, Shiba H, et al. Recombinant thrombomodulin suppresses tumor growth of pancreatic cancer by blocking thrombin-induced PAR1 and NF-kappaB activation[J]. Surgery, 2017, 161(6): 1675-1682 [16] Bazzi ZA, Lanoue D, El-Youssef M, et al. Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates breast cancer cell metastatic behaviors through inhibition of plasminogen activation and extracellular proteolysis[J]. BMC Cancer, 2016, 16: 328 [17] Ross R. Atherosclerosis—An inflammatory disease[J]. N Engl J Med, 1999, 340(2): 115-126 [18] Jaberi N, Soleimani A, Pashirzad M, et al. Role of thrombin in the pathogenesis of atherosclerosis[J]. J Cell Biochem, 2019, 120(4): 4757-4765 [19] Chen PS, Wang KC, Chao TH, et al. Recombinant rhrombomodulin exerts anti-autophagic action in endothelial cells and provides anti-atherosclerosis effect in apolipoprotein E deficient Mice[J]. Sci Rep, 2017, 7(1): 3284 [20] Li YH, Shi GY, Wu HL. The Role of Thrombomodulin in atherosclerosis: from bench to bedside[J]. Cardiovasc Hematol Agents Med Chem, 2006, 4(2): 183-187 [21] Yao G, Qi J, Zhang Z, et al. Endothelial cell injury is involved in atherosclerosis and lupus symptoms in gld. apoE-/- mice[J]. Int J Rheum Dis, 2019, 22(3): 488-496 [22] Pai VC, Lo IC, Huang YW, et al. The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells[J]. J Biomed Sci, 2018, 25(1): 14 [23] Ruscica M, Ferri N, Macchi C, et al. Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?[J]. Ann Med, 2018, 50(6): 461-484 [24] Tanaka K, Salunya T, Motomiya Y, et al. Decreased expression of thrombomodulin in endothelial cells by fibroblast growth factor-23/alpha-Klotho[J]. Ther Apher Dial, 2017, 21(4): 395-404 [25] Wang B, Li T. Efficacy of recombinant human soluble thrombomodulin for acute exacerbation of idiopathic pulmonary fibrosis: A systematic review and meta-analysis[J]. Exp Ther Med, 2020, 20(1): 351-358 [26] Fujiwara K, Kobayashi T, Fujimoto H, et al. Inhibition of cell apoptosis and amelioration of pulmonary fibrosis by thrombomodulin[J]. Am J Pathol, 2017, 187(10): 2312-2322 [27] Collard HR, Calfee CS, Wolters PJ, et al. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis[J]. Am J Physiol Lung Cell Mol Physiol, 2010, 299(1): L3–L7 [28] Arai T, Kida H, Ogata Y, et al. Efficacy of recombinant thrombomodulin for poor prognostic cases of acute exacerbation in idiopathic interstitial pneumonia: secondary analysis of the SETUP trial[J]. BMJ Open Respir Res, 2020, 7(1): e000558 [29] Levi M, Sivapalaratnam S. Disseminated intravascular coagulation: an update on pathogenesis and diagnosis[J]. Expert Rev Hematol, 2018, 11(8): 663-672 [30] Gando S, Levi M, Toh CH. Disseminated intravascular coagulation[J]. Nat Rev Dis Primers, 2016, 2: 16037 [31] Levi M, Sivapalaratnam S. Disseminated intravascular coagulation: an update on pathogenesis and diagnosis[J]. Expert Rev Hematol, 2018, 11(8): 663-672 [32] Madoiwa S. Recent advances in disseminated intravascular coagulation: endothelial cells and fibrinolysis in sepsis-induced DIC[J]. J Intensive Care, 2015, 3: 8 [33] Shin SJ, Hang HT, Thang BQ, et al. Role of PAR1-Egr1 in the Initiation of Thoracic Aortic Aneurysm in Fbln4-Deficient Mice[J]. Arterioscler Thromb Vasc Biol, 2020, 40(8): 1905-1917 [34] Eppensteiner J, Kwun J, Scheuermann U, et al. Damage- and pathogen-associated molecular patterns play differential roles in late mortality after critical illness[J]. JCI Insight, 2019, 4(16): e127925 [35] Tanaka K, Takeba J, Matsumoto H, et al. Anticoagulation therapy using rh-thrombomodulin and/or antithrombin III agent is associated with reduction in in-hospital mortality in septic disseminated intravascular coagulation: a nationwide registry study[J]. Shock, 2019, 51(6): 713-717 [36] Khan KA, McMurray JL, Mohammed F, et al. C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation[J]. FEBS J, 2019, 286(17): 3299-3332 [37] Mukhopadhyay S, Johnson TA, Duru N, et al. Fibrinolysis and Inflammation in Venous Thrombus Resolution[J]. Front Immunol, 2019, 10: 1348 [38] Kroone C, Vos M, Rademakers T, et al. LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis [J]. Haematologica, 2020, 105(6): 1677-1685 [39] Hayashi Y, Tsujita R, Tsubota M, et al. Human soluble thrombomodulin-induced blockade of peripheral HMGB1-dependent allodynia in mice requires both the lectin-like and EGF-like domains[J]. Biochem Biophys Res Commun, 2018, 495(1): 634-638 [40] Crawley JTB, Zalli A, Monkman JH, et al. Defective fibrin deposition and thrombus stability in Bambi-/- mice are mediated by elevated anticoagulant function[J]. Thromb Haemost, 2019, 17(11): 1935-1949 [41] Wendt TM, Nozomu TJ, Guo JC, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy[J]. Am J Pathol, 2003, 162(4): 1123-1137 [42] Haraldsson B, Sörensson J. Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier[J]. News Physiol Sci, 2004, 19: 7-10 [43] Isermann B, Vinnikov IA, Madhusudhan T, et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis[J]. Nat Med, 2007, 13(11): 1349-1358 [44] Ramos JGL, Sass N, Costa SHM. Preeclampsia[J]. Rev Bras Ginecol Obstet, 2017, 39(9): 496-512 [45] Chaiworapongsa T, Chaemsaithong P, Yeo L, et al. Pre-eclampsia part 1: current understanding of its pathophysiology[J]. Nat Rev Nephrol, 2014, 10(8): 466-480 [46] Alpoim PN, Perucci LO, Godoi LC, et al. Oxidative stress markers and thrombomodulin plasma levels in women with early and late severe preeclampsia[J]. Clin Chim Acta, 2018, 483: 234-238 [47] Turner RJ, Bloemenkamp KWM, Brujin JA, et al. Loss of Thrombomodulin in placental dysfunction in preeclampsia[J]. Arterioscler Thromb Vasc Biol, 2016, 36(4): 728-735 [48] Shin M, Hino H, Tamura M, et al. Thrombomodulin improves maternal and fetal conditions in an experimental pre-eclampsia rat model[J]. J Obstet Gynaecol Res, 2014, 40(5): 1226-1234 [49] Kezic A, Stajic N, Thaiss F. Innate immune response in kidney ischemia/reperfusion injury: potential target for therapy[J]. J Immunol Res, 2017, 2017: 6305439 [50] Hayase N, Doi K, Hiruma T, et al. Recombinant thrombomodulin prevents acute lung injury induced by renal ischemia-reperfusion injury[J]. Sci Rep, 2020, 10(1): 289 [51] Laubach VE, Sharma AK. Mechanisms of lung ischemia-reperfusion injury[J]. Curr Opin Organ Transplant, 2016, 21(3): 246-252 [52] Hayase N, Doi K, Hiruma T, et al. Recombinant Thrombomodulin on neutrophil extracellular traps in murine intestinal ischemia–reperfusion[J]. Anesthesiology, 2019, 131(4): 866-882 [53] Hirakawa Y, Tsuchishima M, Fukumura A, et al. Recombinant thrombomodulin prevented hepatic ischemia-reperfusion injury by inhibiting high-mobility group box 1 in rats[J]. Eur J Pharmacol, 2019, 863: 172681
