Targeting thrombomodulin to circulating red blood cells augments its protective effects in models of endotoxemia and ischemia-reperfusion injury

FASEB Journal

Volumn 31, Issue 2, 2017, Pages 761-770

  Carnemolla, Ronald ^a,b   Villa, Carlos H ^a,b   Greineder, Colin F ^a,b   Zaitsev, Sergei ^a,b   Patel, Kruti R ^c   Kowalska, M Anna ^d,e   Atochin, Dmitriy N ^f   Cines, Douglas B ^a   Siegel, Don L ^a   Esmon, Charles T ^g   Muzykantov, Vladimir R ^a,b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b University of Pennsylvania   (United States)

^c BRIGHAM AND WOMEN S HOSPITAL   (United States)

^d CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^e INSTITUTE OF MEDICAL BIOLOGY   (Poland)

^f MASSACHUSETTS GENERAL HOSPITAL   (United States)

^g OKLAHOMA MEDICAL RESEARCH FOUNDATION   (United States)

Author keywords

Coagulation; Drug delivery; Inflammation; Pharmacokinetics; Sepsis

Indexed keywords

ACTIVATED PROTEIN C; ANTIINFLAMMATORY AGENT; ENDOTOXIN; HYBRID PROTEIN; LIPOPOLYSACCHARIDE; NEUROPROTECTIVE AGENT; RECOMBINANT THROMBOMODULIN; SINGLE CHAIN FRAGMENT VARIABLE ANTIBODY; THROMBIN ANTITHROMBIN COMPLEX; THROMBOMODULIN SINGLE CHAIN FRAGMENT VARIABLE ANTIBODY FUSION PROTEIN; UNCLASSIFIED DRUG; MEMBRANE FUSION PROTEIN; THROMBOMODULIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BRAIN ISCHEMIA; CONTROLLED STUDY; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; ENDOTOXEMIA; ERYTHROCYTE; LIVER INJURY; MALE; MOUSE; MOUSE MODEL; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; REPERFUSION INJURY; ANIMAL; C57BL MOUSE; CHEMISTRY; INFLAMMATION; METABOLISM;

ANIMALS; ENDOTOXEMIA; ERYTHROCYTES; INFLAMMATION; MALE; MEMBRANE FUSION PROTEINS; MICE; MICE, INBRED C57BL; REPERFUSION INJURY; THROMBOMODULIN;

EID: 85011255374     PISSN: 08926638     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.201600912R     Document Type: Article

References (68)

1. Esmon, C. T., and Owen, W. G. (2004) The discovery of thrombomodulin. J. Thromb. Haemost. 2, 209-213
2. Conway, E.M. (2012)Thrombomodulin and its role in inflammation. Semin. Immunopathol. 34, 107-125
3. Morser, J. (2012) Thrombomodulin links coagulation to inflammation and immunity. Curr. Drug Targets 13, 421-431
4. Ito, T., andMaruyama, I. (2011)Thrombomodulin: protectorategod of the vasculature in thrombosis and inflammation. J. Thromb. Haemost. 9(Suppl 1), 168-173
5. Bouwens, E. A., Stavenuiter, F., and Mosnier, L. O. (2013) Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J. Thromb. Haemost. 11(Suppl 1), 242-253
6. Mosnier, L. O., Zlokovic, B. V., and Griffin, J. H. (2007) The cytoprotective protein C pathway. Blood 109, 3161-3172
7. Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., and Conway, E. M. (2009) Thrombomodulin mutations inatypicalhemolytic-uremic syndrome. N. Engl. J. Med. 361, 345-357
8. Chang, W.-E., Chang, B.-Y., Ma, C.-Y., Shih, Y.-T., and Cheng, S.-E. (2015) Recombinant thrombomodulin inhibits lipopolysaccharideinduced inflammatory response by blocking the functions of CD14. J. Immunol. 194, 1905-1915
9. Lentz, S.R., Sadler, J.E., andTsiang, M. (1992) Functionaldomains of membrane-bound human thrombomodulin: EGF-like domains four to six and the serine/threonine-richdomainare required for cofactor activity. J. Biol. Chem. 267, 6164-6170
10. Li, Y.-H., Liu, S.-L., Wei, H.-J., Shi, G.-Y., Chang, P.-C., Wu, H.-L., and Kuo, C.-H. (2011) Thrombomodulin domains attenuate atherosclerosis by inhibiting thrombin-induced endothelial cell activation. Cardiovasc. Res. 92, 317-327
11. Lattenist, L., Teske, G., Claessen, N., Florquin, S., Conway, E.M., and Roelofs, J. J. (2015) The lectin like domain of thrombomodulin is involved in the defence against pyelonephritis. Thromb. Res. 136, 1325-1331
12. Li, Y. H., Kuo, C. H., Shi, G. Y., and Wu, H. L. (2012) The role of thrombomodulin lectin-like domain in inflammation. J. Biomed. Sci. 19, 34
13. Abeyama, K., Stern, D. M., Ito, Y., Kawahara, K., Yoshimoto, Y., Tanaka, M., Uchimura, T., Ida, N., Yamazaki, Y., Yamada, S., Yamamoto, Y., Yamamoto, H., Iino, S., Taniguchi, N., and Maruyama, I. (2005) The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J. Clin. Invest. 115, 1267-1274
14. Faust, S. N., Heyderman, R. S., and Levin, M. (2001) Coagulation in severe sepsis: a central role for thrombomodulin and activated protein C. Crit. Care Med. 29, S62-S67
15. Laszik, Z. G., Zhou, X. J., Ferrell, G. L., Silva, F. G., and Esmon, C. T. (2001) Down-regulation of endothelial expression of endothelial cell proteinCreceptor and thrombomodulin in coronary atherosclerosis. Am. J. Pathol. 159, 797-802
16. Hanly, A.M., and Winter, D. C. (2007) The role of thrombomodulin in malignancy. Semin. Thromb. Hemost. 33, 673-679
17. Chan, S. H., Chen, J. H., Li, Y. H., Lin, L. J., and Tsai, L. M. (2006) Increasing post-event plasma thrombomodulin level associates with worse outcome in survival of acute coronary syndrome. Int. J. Cardiol. 111, 280-285
18. Sapru, A., Calfee, C. S., Liu, K. D., Kangelaris, K., Hansen, H., Pawlikowska, L., Ware, L. B., Alkhouli, M. F., Abbott, J., Matthay, M.A., and Network, N. A.; NHLBI ARDS Network. (2015) Plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome. Intensive Care Med. 41, 470-478 [Erratum]
19. Moxon, C. A., Chisala, N. V., Mzikamanda, R., MacCormick, I., Harding, S., Downey, C., Molyneux, M., Seydel, K. B., Taylor, T. E., Heyderman, R. S., and Toh, C. H. (2015) Laboratory evidence of disseminated intravascular coagulation is associated with a fatal outcome in children with cerebral malaria despite an absence of clinically evident thrombosis or bleeding. J. Thromb. Haemost. 13, 1653-1664
20. Dietrich, S., Falk, C. S., Benner, A., Karamustafa, S., Hahn, E., Andrulis, M., Hegenbart, U., Ho, A. D., Dreger, P., and Luft, T. (2013) Endothelial vulnerability and endothelial damage are associated with riskof graft-versus-host disease andresponse tosteroidtreatment. Biol. Blood Marrow Transplant. 19, 22-27
21. Opal, S. M., and LaRosa, S. P. (2013) Recombinant human activated protein C as a therapy for severe sepsis: lessons learned? Am. J. Respir. Crit. Care Med. 187, 1041-1043
22. Martí-Carvajal, A. J., Solà, I., Gluud, C., Lathyris, D., andCardona, A. F. (2012) Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst. Rev. 12, CD004388
23. Angus, D.C. (2012) Drotrecogin alfa (activated). .a sadfinalfizzle to a roller-coaster party. Crit. Care 16, 107
24. Bernard, G. R., Vincent, J. L., Laterre, P. F., LaRosa, S. P., Dhainaut, J. F., Lopez-Rodriguez, A., Steingrub, J. S., Garber, G.E., Helterbrand, J. D., Ely, E. W., and Fisher, C. J., Jr.; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699-709
25. Ranieri, V.M., Thompson, B. T., Barie, P. S., Dhainaut, J. F., Douglas, I. S., Finfer, S., Gårdlund, B., Marshall, J. C., Rhodes, A., Artigas, A., Payen, D., Tenhunen, J., Al-Khalidi, H. R., Thompson, V., Janes, J., Macias, W. L., Vangerow, B., andWilliams, M. D.; PROWESS-SHOCK StudyGroup. (2012)Drotrecogin alfa (activated) in adultswith septic shock. N. Engl. J. Med. 366, 2055-2064
26. Annane, D., Timsit, J. F., Megarbane, B., Martin, C., Misset, B., Mourvillier, B., Siami, S., Chagnon, J. L., Constantin, J. M., Petitpas, F., Souweine, B., Amathieu, R., Forceville, X., Charpentier, C., Tesnière, A., Chastre, J., Bohe, J., Colin, G., Cariou, A., Renault, A., Brun-Buisson, C., Bellissant, E., and Investigators, A. T.; APROCCHSS Trial Investigators. (2013) Recombinant human activated protein C for adults with septic shock: a randomized controlled trial. Am. J. Respir. Crit. Care Med. 187, 1091-1097
27. Aikawa, N., Shimazaki, S., Yamamoto, Y., Saito, H., Maruyama, I., Ohno, R., Hirayama, A., Aoki, Y., and Aoki, N. (2011) Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. Shock 35, 349-354
28. Fink, M. P. (2013) Recombinant soluble thrombomodulin as an adjunctive treatment for sepsis and disseminated intravascular coagulation: relatively safe and possibly effective. Crit. Care Med. 41, 2221-2223
29. Vincent, J. L., Ramesh, M. K., Ernest, D., LaRosa, S. P., Pachl, J., Aikawa, N., Hoste, E., Levy, H., Hirman, J., Levi, M., Daga, M., Kutsogiannis, D. J., Crowther, M., Bernard, G. R., Devriendt, J., Puigserver, J.V., Blanzaco, D. U., Esmon, C.T., Parrillo, J.E., Guzzi, L., Henderson, S. J., Pothirat, C., Mehta, P., Fareed, J., Talwar, D., Tsuruta, K., Gorelick, K. J., Osawa, Y., and Kaul, I. (2013) A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit. CareMed. 41, 2069-2079
30. Shbaklo, H., Holcroft, C. A., and Kahn, S. R. (2009) Levels of inflammatory markers and the development of the post-thrombotic syndrome. Thromb. Haemost. 101, 505-512
31. Andreou, A. P., and Crawley, J. T. (2011) Thrombomodulin analogues for the treatment of ischemic stroke. J. Thromb. Haemost. 9, 1171-1173
32. Esmon, C. T. (2001) Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit. Care Med. 29, S48-S51
33. Van Iersel, T., Stroissnig, H., Giesen, P., Wemer, J., and Wilhelm-Ogunbiyi, K. (2011) Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue. Thromb. Haemost. 105, 302-312
34. Yamakawa, K., Aihara, M., Ogura, H., Yuhara, H., Hamasaki, T., and Shimazu, T. (2015) Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis. J. Thromb. Haemost. 13, 508-519
35. Levi, M. (2015) Recombinant soluble thrombomodulin: coagulation takes another chance to reduce sepsis mortality. J. Thromb. Haemost. 13, 505-507
36. Zaitsev, S., Kowalska, M. A., Neyman, M., Carnemolla, R., Tliba, S., Ding, B. S., Stonestrom, A., Spitzer, D., Atkinson, J. P., Poncz, M., Cines, D. B., Esmon, C. T., and Muzykantov, V. R. (2012) Targeting recombinant thrombomodulin fusion protein to red blood cells provides multifaceted thromboprophylaxis. Blood 119, 4779-4785
37. Ding, B. S., Hong, N., Christofidou-Solomidou, M., Gottstein, C., Albelda, S.M., Cines, D.B., Fisher, A.B., andMuzykantov, V.R. (2009) Anchoring fusion thrombomodulin to the endothelial lumen protects against injury-induced lung thrombosis and inflammation. Am. J. Respir. Crit. Care Med. 180, 247-256
38. Greineder, C. F., Chacko, A. M., Zaytsev, S., Zern, B. J., Carnemolla, R., Hood, E. D., Han, J., Ding, B. S., Esmon, C. T., andMuzykantov, V. R. (2013) Vascular immunotargeting to endothelial determinant ICAM-1 enables optimal partnering of recombinant scFv-thrombomodulin fusion with endogenous cofactor. PLoS One 8, e80110
39. Carnemolla, R., Greineder, C. F., Chacko, A. M., Patel, K. R., Ding, B. S., Zaitsev, S., Esmon, C. T., andMuzykantov, V. R. (2013) Platelet endothelial cell adhesionmolecule targeted oxidant-resistantmutant thrombomodulin fusion protein with enhanced potency in vitro and in vivo. J. Pharmacol. Exp. Ther. 347, 339-345
40. Mohan Rao, L. V., Esmon, C.T., andPendurthi, U. R. (2014)Endothelial cell protein C receptor: a multiliganded and multifunctional receptor. Blood 124, 1553-1562
41. Ganguly, K., Murciano, J. C., Westrick, R., Leferovich, J., Cines, D. B., and Muzykantov, V. R. (2007) The glycocalyx protects erythrocytebound tissue-type plasminogen activator from enzymatic inhibition. J. Pharmacol. Exp. Ther. 321, 158-164
42. Schouten, M., van 't Veer, C., Poulussen, N., Meijers, J. C., Levi, M., Esmon, C.T., and van der Poll, T. (2015)The cytoprotective effects of endogenous activated protein C reduce activation of coagulation during murine pneumococcal pneumonia and sepsis. Thromb. Res. 135, 537-543
43. Liaw, P. C., Ferrell, G., and Esmon, C. T. (2003) A monoclonal antibody against activated protein C allows rapid detection of activated protein C in plasma and reveals a calcium ion dependent epitope involved in factor Va inactivation. J. Thromb. Haemost. 1, 662-670
44. Shuvaev, V. V., Han, J., Tliba, S., Arguiri, E., Christofidou-Solomidou, M., Ramirez, S. H., Dykstra, H., Persidsky, Y., Atochin, D.N., Huang, P. L., andMuzykantov, V. R. (2013) Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo. PLoS One 8, e77002
45. Atochin, D. N., Schepetkin, I. A., Khlebnikov, A. I., Seledtsov, V. I., Swanson, H., Quinn, M. T., and Huang, P. L. (2016) A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia-reperfusion injury in mice. Neurosci. Lett. 618, 45-49
46. Sun, P., Li, Q., Zhang, Q., Xu, L., and Han, J. Y. (2013) Upregulated expression of S100A8 in mice brain after focal cerebral ischemia reperfusion. World J. Emerg. Med. 4, 210-214
47. Carnemolla, R., Patel, K.R., Zaitsev, S., Cines, D. B., Esmon, C. T., and Muzykantov, V. R. (2012) Quantitative analysis of thrombomodulinmediated conversion of protein C to APC: translation fromin vitro to in vivo. J. Immunol. Methods 384, 21-24
48. Pawlinski, R., Wang, J. G., Owens III, A. P., Williams, J., Antoniak, S., Tencati, M., Luther, T., Rowley, J.W., Low, E. N., Weyrich, A. S., and Mackman, N. (2010) Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice. Blood 116, 806-814
49. Xu, J., Ji, Y., Zhang, X., Drake, M., and Esmon, C. T. (2009) Endogenous activated protein C signaling is critical to protection of mice fromlipopolysaccaride-induced septic shock. J.Thromb.Haemost. 7, 851-856
50. Bongoni, A. K., Klymiuk, N., Wolf, E., Ayares, D., Rieben, R., and Cowan, P. J. (2016) Transgenic expression of human thrombomodulin inhibits HMGB1-induced porcine aortic endothelial cell activation. Transplantation 100, 1871-1879
51. Tanaka, J., Seki, Y., Ishikura, H., Tsubota, M., Sekiguchi, F., Yamaguchi, K., Murai, A., Umemura, T., and Kawabata, A. (2013) Recombinant human soluble thrombomodulin prevents peripheral HMGB1-dependent hyperalgesia in rats. Br. J. Pharmacol. 170, 1233-1241
52. Ito, T., Kawahara, K., Okamoto, K., Yamada, S., Yasuda, M., Imaizumi, H., Nawa, Y., Meng, X., Shrestha, B., Hashiguchi, T., andMaruyama, I. (2008) Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arterioscler. Thromb. Vasc. Biol. 28, 1825-1830
53. Su, E. J., Geyer, M., Wahl, M., Mann, K., Ginsburg, D., Brohmann, H., Petersen, K. U., and Lawrence, D. A. (2011) The thrombomodulin analog Solulin promotes reperfusion and reduces infarct volume in a thrombotic stroke model. J. Thromb. Haemost. 9, 1174-1182
54. Morris, G. P., Wright, A. L., Tan, R. P., Gladbach, A., Ittner, L.M., and Vissel, B. (2016) A comparative study of variables influencing ischemic injury in the Longa and Koizumi methods of intraluminal filament middle cerebral artery occlusion in mice. PLoS One 11, e0148503
55. Ryang, Y. M., Dang, J., Kipp, M., Petersen, K. U., Fahlenkamp, A. V., Gempt, J., Wesp, D., Rossaint, R., Beyer, C., and Coburn, M. (2011) Solulin reduces infarct volume and regulates gene-expression in transient middle cerebral artery occlusion in rats. BMC Neurosci. 12, 113
56. Geiger, H., Pawar, S.A., Kerschen, E. J., Nattamai, K. J., Hernandez, I., Liang, H. P., Fernández, J. A., Cancelas, J. A., Ryan, M. A., Kustikova, O., Schambach, A., Fu, Q., Wang, J., Fink, L.M., Petersen, K.U., Zhou, D., Griffin, J. H., Baum, C., Weiler, H., and Hauer-Jensen, M. (2012) Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat. Med. 18, 1123-1129
57. Suyama, K., Kawasaki, Y., Miyazaki, K., Kanno, S., Ono, A., Ohara, S., Sato, M., andHosoya, M. (2015) The efficacy of recombinant human soluble thrombomodulin for the treatment of shiga toxin-associated hemolytic uremic syndromemodelmice.Nephrol. Dial. Transplant. 30, 969-977
58. Tanemura, A., Kuriyama, N., Azumi, Y., Ohsawa, I., Kishiwada, M., Mizuno, S., Usui, M., Sakurai, H., Tabata, M., and Isaji, S. (2014) Thrombomodulin administration attenuates ischemia-reperfusion injury of the remnant liver after 70% hepatectomy in rats: simulated model of small-for-size graft in living donor liver transplantation. Transplant. Proc. 46, 1107-1111
59. Ikezoe, T., Yang, J., Nishioka, C., and Yokoyama, A. (2015) Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen. Bone Marrow Transplant. 50, 113-120
60. Villa, C. H., Anselmo, A. C., Mitragotri, S., and Muzykantov, V. (2016) Red blood cells: supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems.Adv. Drug Deliv. Rev.S0169-409X(16)30058-8
61. Murciano, J.C., Medinilla, S., Eslin, D., Atochina, E., Cines, D. B., and Muzykantov, V. R. (2003) Prophylactic fibrinolysis through selective dissolution of nascent clots by tPA-carrying erythrocytes. Nat. Biotechnol. 21, 891-896
62. Medinilla, S., Murciano, J. C., Krasik, T., Bdeir, K., Ganguly, K., Muzykantov, V. R., and Cines, D. B. (2005) Blood clearance and activity of erythrocyte-coupled fibrinolytics. J. Pharmacol. Exp. Ther. 312, 1106-1113
63. Murciano, J. C., Higazi, A. A.-R., Cines, D. B., and Muzykantov, V. R. (2009) Soluble urokinase receptor conjugated to carrier red blood cells binds latent pro-urokinase and alters its functional profile. J. Control. Release 139, 190-196
64. Zaitsev, S., Spitzer, D., Murciano, J.-C., Ding, B.-S., Tliba, S., Kowalska, M. A., Marcos-Contreras, O. A., Kuo, A., Stepanova, V., Atkinson, J. P., Poncz, M., Cines, D. B., Muzykantov, V. R., Marcos-Contreras, O. A., Kuo, A., Atkinson, J. P., Stepanova, V., Kowalska, M.A., Tliba, S., Ding, B.-S., Zaitsev, S., Spitzer, D., and Poncz, M. (2010) Sustained thromboprophylaxis mediated by an RBC-targeted pro-urokinase zymogen activated at the site of clot formation. Blood 115, 5241-5248
65. Villa, C. H., Muzykantov, V.R., andCines, D.B. (2016)The emerging role for red blood cells in haemostasis: opportunity for intervention. ISBT Sci. Ser. 11, 158
66. Paulitschke, M., Nash, G. B., Anstee, D. J., Tanner, M. J., and Gratzer, W. B. (1995) Perturbation of red blood cell membrane rigidity by extracellular ligands. Blood 86, 342-348
67. Chasis, J. A., Mohandas, N., and Shohet, S. B. (1985) Erythrocyte membrane rigidity induced by glycophorin A-ligand interaction: evidence for a ligand-induced association between glycophorin A and skeletal proteins. J. Clin. Invest. 75, 1919-1926
68. Khoory, J., Estanislau, J., Elkhal, A., Lazaar, A., Melhorn, M. I., Brodsky, A., Illigens, B., Hamachi, I., Kurishita, Y., Ivanov, A. R., Shevkoplyas, S., Shapiro, N. I., and Ghiran, I. C. (2016) Ligation of glycophorinAgenerates reactive oxygen species leading to decreased red blood cell function. PLoS One 11, e0141206