Haptoglobin, hemopexin and related defense pathways-basic science, clinical perspectives and drug development

Frontiers in Physiology

Volumn 5, Issue OCT, 2014, Pages

  Schaer, Dominik J ^a   Vinchi, Francesca ^b   Ingoglia, Giada ^b   Tolosano, Emanuela ^b   Buehler, Paul W ^c  

^a UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^b UNIVERSITY OF TURIN   (Italy)

^c CENTER FOR BIOLOGICS EVALUATION AND RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD163 ANTIGEN; HAPTOGLOBIN; HEMOPEXIN; INTERLEUKIN 6; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN; NITRIC OXIDE; TOLL LIKE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA;

AEROBIC METABOLISM; ARTICLE; ATHEROSCLEROSIS; BINDING AFFINITY; BLOOD VESSEL INJURY; CARDIOVASCULAR DISEASE; CELL METABOLISM; CORONARY ARTERY DISEASE; DETOXIFICATION; HALF LIFE TIME; HEMOLYTIC ANEMIA; HUMAN; KIDNEY FAILURE; LIPID PEROXIDATION; LIVER CELL; MACROPHAGE; MONOCYTE; NONHUMAN; PHENOTYPE; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN HOMEOSTASIS; PROTEIN INTERACTION; PROTEIN POLYMORPHISM; PROTEIN SYNTHESIS; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION;

EID: 84908373728     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2014.00415     Document Type: Article

References (117)

1. Ackers, G.K., and Halvorson, H.R. (1974). The linkage between oxygenation and subunit dissociation in human hemoglobin. Proc Natl Acad Sci U S A 71, 4312-4316.
2. Andersen, C.B., Torvund-Jensen, M., Nielsen, M.J., De Oliveira, C.L., Hersleth, H.P., Andersen, N.H., Pedersen, J.S., Andersen, G.R., and Moestrup, S.K. (2012). Structure of the haptoglobinhaemoglobin complex. Nature 489, 456-459.
3. Andersen, M.N., Mouritzen, C.V., and Gabrielli, E.R. (1966). Mechanisms of plasma hemoglobin clearance after acute hemolysis in dogs: serum haptoglobin levels and selective deposition in liver and kidney. Ann Surg 164, 905-912.
4. Asleh, R., Guetta, J., Kalet-Litman, S., Miller-Lotan, R., and Levy, A.P. (2005). Haptoglobin genotypeand diabetes-dependent differences in iron-mediated oxidative stress in vitro and in vivo. Circ Res 96, 435-441.
5. Asleh, R., Marsh, S., Shilkrut, M., Binah, O., Guetta, J., Lejbkowicz, F., Enav, B., Shehadeh, N., Kanter, Y., Lache, O., Cohen, O., Levy, N.S., and Levy, A.P. (2003). Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ Res 92, 1193-1200.
6. Azarov, I., He, X., Jeffers, A., Basu, S., Ucer, B., Hantgan, R.R., Levy, A., and Kim-Shapiro, D.B. (2008). Rate of nitric oxide scavenging by hemoglobin bound to haptoglobin. Nitric Oxide 18, 296-302.
7. Bachli, E.B., Schaer, D.J., Walter, R.B., Fehr, J., and Schoedon, G. (2006). Functional expression of the CD163 scavenger receptor on acute myeloid leukemia cells of monocytic lineage. J Leukoc Biol 79, 312-318.
8. Baek, J.H., D'agnillo, F., Vallelian, F., Pereira, C.P., Williams, M.C., Jia, Y., Schaer, D.J., and Buehler, P.W. (2012). Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy. J Clin Invest 122, 1444-1458.
9. Baek, J.H., Zhang, X., Williams, M.C., Schaer, D.J., Buehler, P.W., and D'agnillo, F. (2014). Extracellular Hb enhances cardiac toxicity in endotoxemic guinea pigs: protective role of haptoglobin. Toxins (Basel) 6, 1244-1259.
10. Balla, G., Jacob, H.S., Eaton, J.W., Belcher, J.D., and Vercellotti, G.M. (1991). Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury. Arterioscler Thromb 11, 1700-1711.
11. Balla, J., Jacob, H.S., Balla, G., Nath, K., Eaton, J.W., and Vercellotti, G.M. (1993). Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. Proc Natl Acad Sci U S A 90, 9285-9289.
12. Ballarin, J., Arce, Y., Torra Balcells, R., Diaz Encarnacion, M., Manzarbeitia, F., Ortiz, A., Egido, J., and Moreno, J.A. (2011). Acute renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular haemosiderin accumulation and CD163 expression. Nephrol Dial Transplant 26, 3408-3411.
13. Belcher, J.D., Beckman, J.D., Balla, G., Balla, J., and Vercellotti, G. (2010). Heme degradation and vascular injury. Antioxid Redox Signal 12, 233-248.
14. Belcher, J.D., Bryant, C.J., Nguyen, J., Bowlin, P.R., Kielbik, M.C., Bischof, J.C., Hebbel, R.P., and Vercellotti, G.M. (2003). Transgenic sickle mice have vascular inflammation. Blood 101, 3953-3959.
15. Belcher, J.D., Chen, C., Nguyen, J., Milbauer, L., Abdulla, F., Alayash, A.I., Smith, A., Nath, K.A., Hebbel, R.P., and Vercellotti, G.M. (2014). Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123, 377-390.
16. Belcher, J.D., Marker, P.H., Weber, J.P., Hebbel, R.P., and Vercellotti, G.M. (2000). Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood 96, 2451-2459.
17. Billings, F.T.T., Ball, S.K., Roberts, L.J., II, and Pretorius, M. (2011). Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response. Free Radic Biol Med 50, 1480-1487.
18. Boretti, F.S., Buehler, P.W., D'agnillo, F., Kluge, K., Glaus, T., Butt, O.I., Jia, Y., Goede, J., Pereira, C.P., Maggiorini, M., Schoedon, G., Alayash, A.I., and Schaer, D.J. (2009). Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs. J Clin Invest 119, 2271-2280.
19. Boutaud, O., Moore, K.P., Reeder, B.J., Harry, D., Howie, A.J., Wang, S., Carney, C.K., Masterson, T.S., Amin, T., Wright, D.W., Wilson, M.T., Oates, J.A., and Roberts, L.J., II (2010). Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure. Proc Natl Acad Sci U S A 107, 2699-2704.
20. Boyle, J.J., Harrington, H.A., Piper, E., Elderfield, K., Stark, J., Landis, R.C., and Haskard, D.O. (2009). Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 174, 1097-1108.
21. Boyle, J.J., Johns, M., Kampfer, T., Nguyen, A.T., Game, L., Schaer, D.J., Mason, J.C., and Haskard, D.O. (2012). Activating transcription factor 1 directs Mhem atheroprotective macrophages through coordinated iron handling and foam cell protection. Circ Res 110, 20-33.
22. Buechler, C., Ritter, M., Orso, E., Langmann, T., Klucken, J., and Schmitz, G. (2000). Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 67, 97-103.
23. Buehler, P.W., Abraham, B., Vallelian, F., Linnemayr, C., Pereira, C.P., Cipollo, J.F., Jia, Y., Mikolajczyk, M., Boretti, F.S., Schoedon, G., Alayash, A.I., and Schaer, D.J. (2009). Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification. Blood 113, 2578-2586.
24. Buehler, P.W., D'agnillo, F., Hoffman, V., and Alayash, A.I. (2007). Effects of endogenous ascorbate on oxidation, oxygenation, and toxicokinetics of cell-free modified hemoglobin after exchange transfusion in rat and guinea pig. J Pharmacol Exp Ther 323, 49-60.
25. Buehler, P.W., D'agnillo, F., and Schaer, D.J. (2010). Hemoglobin-based oxygen carriers: From mechanisms of toxicity and clearance to rational drug design. Trends Mol Med 16, 447-457.
26. Buehler, P.W., Vallelian, F., Mikolajczyk, M.G., Schoedon, G., Schweizer, T., Alayash, A.I., and Schaer, D.J. (2008). Structural stabilization in tetrameric or polymeric hemoglobin determines its interaction with endogenous antioxidant scavenger pathways. Antioxid Redox Signal 10, 1449-1462.
27. Bunn, H.F., Esham, W.T., and Bull, R.W. (1969). The renal handling of hemoglobin. I. Glomerular filtration. J Exp Med 129, 909-923.
28. Bunn, H.F., and Jandl, J.H. (1968). Exchange of heme among hemoglobins and between hemoglobin and albumin. J Biol Chem 243, 465-475.
29. Butt, O.I., Buehler, P.W., and D'agnillo, F. (2010). Differential induction of renal heme oxygenase and ferritin in ascorbate and nonascorbate producing species transfused with modified cell-free hemoglobin. Antioxid Redox Signal 12, 199-208.
30. Cahill, L.E., Levy, A.P., Chiuve, S.E., Jensen, M.K., Wang, H., Shara, N.M., Blum, S., Howard, B.V., Pai, J.K., Mukamal, K.J., Rexrode, K.M., and Rimm, E.B. (2013). Haptoglobin genotype is a consistent marker of coronary heart disease risk among individuals with elevated glycosylated hemoglobin. J Am Coll Cardiol 61, 728-737.
31. Chiabrando, D., Vinchi, F., Fiorito, V., Mercurio, S., and Tolosano, E. (2014). Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front Pharmacol 5, 61.
32. Cid, M.C., Grant, D.S., Hoffman, G.S., Auerbach, R., Fauci, A.S., and Kleinman, H.K. (1993). Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis. J Clin Invest 91, 977-985.
33. Cooper, C.E., Schaer, D.J., Buehler, P.W., Wilson, M.T., Reeder, B.J., Silkstone, G., Svistunenko, D.A., Bulow, L., and Alayash, A.I. (2012). Haptoglobin Binding Stabilizes Hemoglobin Ferryl Iron and the Globin Radical on Tyrosine beta145. Antioxid Redox Signal.
34. Dalton, J., and Podmore, A. (2011). Enriched haptoglobin polymers for the treatment of disease. US Patent Application 20110021418.
35. Delanghe, J., Allcock, K., Langlois, M., Claeys, L., and De Buyzere, M. (2000). Fast determination of haptoglobin phenotype and calculation of hemoglobin binding capacity using high pressure gel permeation chromatography. Clin Chim Acta 291, 43-51.
36. Doherty, D.H., Doyle, M.P., Curry, S.R., Vali, R.J., Fattor, T.J., Olson, J.S., and Lemon, D.D. (1998). Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nat Biotechnol 16, 672-676.
37. Droste, A., Sorg, C., and Hogger, P. (1999). Shedding of CD163, a novel regulatory mechanism for a member of the scavenger receptor cysteine-rich family. Biochem Biophys Res Commun 256, 110-113.
38. Etzerodt, A., Kjolby, M., Nielsen, M.J., Maniecki, M., Svendsen, P., and Moestrup, S.K. (2012). Plasma Clearance of Hemoglobin and Haptoglobin in Mice and Effect of CD163 Gene Targeting Disruption. Antioxid Redox Signal.
39. Etzerodt, A., Maniecki, M.B., Moller, K., Moller, H.J., and Moestrup, S.K. (2010). Tumor necrosis factor alpha-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163. J Leukoc Biol 88, 1201-1205.
40. Faivre-Fiorina, B., Caron, A., Fassot, C., Fries, I., Menu, P., Labrude, P., and Vigneron, C. (1999). Presence of hemoglobin inside aortic endothelial cells after cell-free hemoglobin administration in guinea pigs. Am J Physiol 276, H766-770.
41. Figueiredo, R.T., Fernandez, P.L., Mourao-Sa, D.S., Porto, B.N., Dutra, F.F., Alves, L.S., Oliveira, M.F., Oliveira, P.L., Graca-Souza, A.V., and Bozza, M.T. (2007). Characterization of heme as activator of Toll-like receptor 4. J Biol Chem 282, 20221-20229.
42. Finn, A.V., Nakano, M., Polavarapu, R., Karmali, V., Saeed, O., Zhao, X., Yazdani, S., Otsuka, F., Davis, T., Habib, A., Narula, J., Kolodgie, F.D., and Virmani, R. (2012). Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol 59, 166-177.
43. Fortes, G.B., Alves, L.S., De Oliveira, R., Dutra, F.F., Rodrigues, D., Fernandez, P.L., Souto-Padron, T., De Rosa, M.J., Kelliher, M., Golenbock, D., Chan, F.K., and Bozza, M.T. (2012). Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. Blood 119, 2368-2375.
44. Galicia, G., Maes, W., Verbinnen, B., Kasran, A., Bullens, D., Arredouani, M., and Ceuppens, J.L. (2009). Haptoglobin deficiency facilitates the development of autoimmune inflammation. Eur J Immunol 39, 3404-3412.
45. Gattoni, M., Boffi, A., Sarti, P., and Chiancone, E. (1996). Stability of the heme-globin linkage in alphabeta dimers and isolated chains of human hemoglobin. A study of the heme transfer reaction from the immobilized proteins to albumin. J Biol Chem 271, 10130-10136.
46. Ghosh, S., Adisa, O.A., Chappa, P., Tan, F., Jackson, K.A., Archer, D.R., and Ofori-Acquah, S.F. (2013). Extracellular hemin crisis triggers acute chest syndrome in sickle mice. J Clin Invest 123, 4809-4820.
47. Gladwin, M.T., Kanias, T., and Kim-Shapiro, D.B. (2012). Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease. J Clin Invest 122, 1205-1208.
48. Gladwin, M.T., Sachdev, V., Jison, M.L., Shizukuda, Y., Plehn, J.F., Minter, K., Brown, B., Coles, W.A., Nichols, J.S., Ernst, I., Hunter, L.A., Blackwelder, W.C., Schechter, A.N., Rodgers, G.P., Castro, O., and Ognibene, F.P. (2004). Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 350, 886-895.
49. Griffon, N., Baudin, V., Dieryck, W., Dumoulin, A., Pagnier, J., Poyart, C., and Marden, M.C. (1998). Tetramer-dimer equilibrium of oxyhemoglobin mutants determined from auto-oxidation rates. Protein Sci 7, 673-680.
50. Hashimoto, K., Nomura, K., Nakano, M., Sasaki, T., and Kurosawa, H. (1993). Pharmacological intervention for renal protection during cardiopulmonary bypass. Heart Vessels 8, 203-210.
51. Hintz, K.A., Rassias, A.J., Wardwell, K., Moss, M.L., Morganelli, P.M., Pioli, P.A., Givan, A.L., Wallace, P.K., Yeager, M.P., and Guyre, P.M. (2002). Endotoxin induces rapid metalloproteinasemediated shedding followed by up-regulation of the monocyte hemoglobin scavenger receptor CD163. J Leukoc Biol 72, 711-717.
52. Homann, B., Kult, J., and Weis, K.H. (1977). [On the use of concentrated haptoglobin in the treatment of a haemolytic transfusion accident of the ABO-system (author's transl)]. Anaesthesist 26, 485-488.
53. Hvidberg, V., Maniecki, M.B., Jacobsen, C., Hojrup, P., Moller, H.J., and Moestrup, S.K. (2005). Identification of the receptor scavenging hemopexin-heme complexes. Blood 106, 2572-2579.
54. Imaizumi, H., Tsunoda, K., Ichimiya, N., Okamoto, T., and Namiki, A. (1994). Repeated large-dose haptoglobin therapy in an extensively burned patient: case report. J Emerg Med 12, 33-37.
55. Janz, D.R., Bastarache, J.A., Sills, G., Wickersham, N., May, A.K., Bernard, G.R., and Ware, L.B. (2013). Association between haptoglobin, hemopexin and mortality in adults with sepsis. Crit Care 17, R272.
56. Jeney, V., Balla, J., Yachie, A., Varga, Z., Vercellotti, G.M., Eaton, J.W., and Balla, G. (2002). Prooxidant and cytotoxic effects of circulating heme. Blood 100, 879-887.
57. Jia, Y., Buehler, P.W., Boykins, R.A., Venable, R.M., and Alayash, A.I. (2007). Structural basis of peroxide-mediated changes in human hemoglobin: a novel oxidative pathway. J Biol Chem 282, 4894-4907.
58. Kaempfer, T., Duerst, E., Gehrig, P., Roschitzki, B., Rutishauser, D., Grossmann, J., Schoedon, G., Vallelian, F., and Schaer, D.J. (2011). Extracellular hemoglobin polarizes the macrophage proteome toward Hb-clearance, enhanced antioxidant capacity and suppressed HLA class 2 expression. J Proteome Res 10, 2397-2408.
59. Kamboh, M.I., Bunker, C.H., Nwankwo, M.U., and Ferrell, R.E. (1993). Hemopexin: a unique genetic polymorphism in populations of African ancestry. Hum Biol 65, 655-660.
60. Komarova, Y., and Malik, A.B. (2010). Regulation of endothelial permeability via paracellular and transcellular transport pathways. Annu Rev Physiol 72, 463-493.
61. Kormoczi, G.F., Saemann, M.D., Buchta, C., Peck-Radosavljevic, M., Mayr, W.R., Schwartz, D.W., Dunkler, D., Spitzauer, S., and Panzer, S. (2006). Influence of clinical factors on the haemolysis marker haptoglobin. Eur J Clin Invest 36, 202-209.
62. Kristiansen, M., Graversen, J.H., Jacobsen, C., Sonne, O., Hoffman, H.J., Law, S.K., and Moestrup, S.K. (2001). Identification of the haemoglobin scavenger receptor. Nature 409, 198-201.
63. Langlois, M.R., and Delanghe, J.R. (1996). Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem 42, 1589-1600.
64. Larsen, R., Gozzelino, R., Jeney, V., Tokaji, L., Bozza, F.A., Japiassu, A.M., Bonaparte, D., Cavalcante, M.M., Chora, A., Ferreira, A., Marguti, I., Cardoso, S., Sepulveda, N., Smith, A., and Soares, M.P. (2010). A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2, 51ra71.
65. Law, S.K., Micklem, K.J., Shaw, J.M., Zhang, X.P., Dong, Y., Willis, A.C., and Mason, D.Y. (1993). A new macrophage differentiation antigen which is a member of the scavenger receptor superfamily. Eur J Immunol 23, 2320-2325.
66. Levy, A.P., Asleh, R., Blum, S., Levy, N.S., Miller-Lotan, R., Kalet-Litman, S., Anbinder, Y., Lache, O., Nakhoul, F.M., Asaf, R., Farbstein, D., Pollak, M., Soloveichik, Y.Z., Strauss, M., Alshiek, J., Livshits, A., Schwartz, A., Awad, H., Jad, K., and Goldenstein, H. (2010). Haptoglobin: basic and clinical aspects. Antioxid Redox Signal 12, 293-304.
67. Levy, A.P., Purushothaman, K.R., Levy, N.S., Purushothaman, M., Strauss, M., Asleh, R., Marsh, S., Cohen, O., Moestrup, S.K., Moller, H.J., Zias, E.A., Benhayon, D., Fuster, V., and Moreno, P.R. (2007). Downregulation of the hemoglobin scavenger receptor in individuals with diabetes and the Hp 2-2 genotype: implications for the response to intraplaque hemorrhage and plaque vulnerability. Circ Res 101, 106-110.
68. Liang, X., Lin, T., Sun, G., Beasley-Topliffe, L., Cavaillon, J.M., and Warren, H.S. (2009). Hemopexin down-regulates LPS-induced proinflammatory cytokines from macrophages. J Leukoc Biol 86, 229-235.
69. Lin, S., Yin, Q., Zhong, Q., Lv, F.L., Zhou, Y., Li, J.Q., Wang, J.Z., Su, B.Y., and Yang, Q.W. (2012a). Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. J Neuroinflammation 9, 46.
70. Lin, T., Sammy, F., Yang, H., Thundivalappil, S., Hellman, J., Tracey, K.J., and Warren, H.S. (2012b). Identification of hemopexin as an anti-inflammatory factor that inhibits synergy of hemoglobin with HMGB1 in sterile and infectious inflammation. J Immunol 189, 2017-2022.
71. Lipiski, M., Deuel, J., Baek, J.H., Engelsberger, W.R., Buehler, P.W., and Schaer, D.J. (2013). Human phenotype specific haptoglobin therapeutics are both effective in vitro and in vivo to attenuate hemoglobin toxicity in guinea pigs. Antioxid Redox Signal.
72. Madsen, M., Moller, H.J., Nielsen, M.J., Jacobsen, C., Graversen, J.H., Van Den Berg, T., and Moestrup, S.K. (2004). Molecular characterization of the haptoglobin.hemoglobin receptor CD163. Ligand binding properties of the scavenger receptor cysteine-rich domain region. J Biol Chem 279, 51561-51567.
73. Marinkovic, S., and Baumann, H. (1990). Structure, hormonal regulation, and identification of the interleukin-6- and dexamethasone-responsive element of the rat haptoglobin gene. Mol Cell Biol 10, 1573-1583.
74. Matheson, B., Razynska, A., Kwansa, H., and Bucci, E. (2000). Appearance of dissociable and crosslinked hemoglobins in the renal hilar lymph. J Lab Clin Med 135, 459-464.
75. Miller, Y.I., Altamentova, S.M., and Shaklai, N. (1997). Oxidation of low-density lipoprotein by hemoglobin stems from a heme-initiated globin radical: antioxidant role of haptoglobin. Biochemistry 36, 12189-12198.
76. Minneci, P.C., Deans, K.J., Zhi, H., Yuen, P.S., Star, R.A., Banks, S.M., Schechter, A.N., Natanson, C., Gladwin, M.T., and Solomon, S.B. (2005). Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin. J Clin Invest 115, 3409-3417.
77. Mollan, T.L., Jia, Y., Banerjee, S., Wu, G., Kreulen, R.T., Tsai, A.L., Olson, J.S., Crumbliss, A.L., and Alayash, A.I. (2014). Redox properties of human hemoglobin in complex with fractionated dimeric and polymeric human haptoglobin. Free Radic Biol Med 69, 265-277.
78. Moller, H.J., Moestrup, S.K., Weis, N., Wejse, C., Nielsen, H., Pedersen, S.S., Attermann, J., Nexo, E., and Kronborg, G. (2006). Macrophage serum markers in pneumococcal bacteremia: Prediction of survival by soluble CD163. Crit Care Med 34, 2561-2566.
79. Moller, H.J., Peterslund, N.A., Graversen, J.H., and Moestrup, S.K. (2002). Identification of the hemoglobin scavenger receptor/CD163 as a natural soluble protein in plasma. Blood 99, 378-380.
80. Moreno, P.R., Purushothaman, K.R., Purushothaman, M., Muntner, P., Levy, N.S., Fuster, V., Fallon, J.T., Lento, P.A., Winterstern, A., and Levy, A.P. (2008). Haptoglobin genotype is a major determinant of the amount of iron in the human atherosclerotic plaque. J Am Coll Cardiol 52, 1049-1051.
81. Muller-Eberhard, U., Javid, J., Liem, H.H., Hanstein, A., and Hanna, M. (1968). Plasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases. Blood 32, 811-815.
82. Murray, R.K., Connell, G.E., and Pert, J.H. (1961). The role of haptoglobin in the clearance and distribution of extracorpuscular hemoglobin. Blood 17, 45-53.
83. Nagy, E., Eaton, J.W., Jeney, V., Soares, M.P., Varga, Z., Galajda, Z., Szentmiklosi, J., Mehes, G., Csonka, T., Smith, A., Vercellotti, G.M., Balla, G., and Balla, J. (2010). Red cells, hemoglobin, heme, iron, and atherogenesis. Arterioscler Thromb Vasc Biol 30, 1347-1353.
84. Nakai, K., Sakuma, I., Ohta, T., Ando, J., Kitabatake, A., Nakazato, Y., and Takahashi, T.A. (1998). Permeability characteristics of hemoglobin derivatives across cultured endothelial cell monolayers. J Lab Clin Med 132, 313-319.
85. Natanson, C., Kern, S.J., Lurie, P., Banks, S.M., and Wolfe, S.M. (2008). Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. JAMA 299, 2304-2312.
86. Niethammer, P., Grabher, C., Look, A.T., and Mitchison, T.J. (2009). A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459, 996-999.
87. Olson, J.S., Foley, E.W., Rogge, C., Tsai, A.L., Doyle, M.P., and Lemon, D.D. (2004). NO scavenging and the hypertensive effect of hemoglobin-based blood substitutes. Free Radic Biol Med 36, 685-697.
88. Pimenova, T., Pereira, C.P., Gehrig, P., Buehler, P.W., Schaer, D.J., and Zenobi, R. (2010). Quantitative mass spectrometry defines an oxidative hotspot in hemoglobin that is specifically protected by haptoglobin. J Proteome Res 9, 4061-4070.
89. Pimenova, T., Pereira, C.P., Schaer, D.J., and Zenobi, R. (2009). Characterization of high molecular weight multimeric states of human haptoglobin and hemoglobin-based oxygen carriers by high-mass MALDI MS. J Sep Sci 32, 1224-1230.
90. Purushothaman, K.R., Purushothaman, M., Levy, A.P., Lento, P.A., Evrard, S., Kovacic, J.C., Briley-Saebo, K.C., Tsimikas, S., Witztum, J.L., Krishnan, P., Kini, A., Fayad, Z.A., Fuster, V., Sharma, S.K., and Moreno, P.R. (2012). Increased expression of oxidation-specific epitopes and apoptosis are associated with haptoglobin genotype: possible implications for plaque progression in human atherosclerosis. J Am Coll Cardiol 60, 112-119.
91. Qian, Q., Nath, K.A., Wu, Y., Daoud, T.M., and Sethi, S. (2010). Hemolysis and acute kidney failure. Am J Kidney Dis 56, 780-784.
92. Reeder, B.J., Grey, M., Silaghi-Dumitrescu, R.L., Svistunenko, D.A., Bulow, L., Cooper, C.E., and Wilson, M.T. (2008). Tyrosine residues as redox cofactors in human hemoglobin: implications for engineering nontoxic blood substitutes. J Biol Chem 283, 30780-30787.
93. Reiter, C.D., Wang, X., Tanus-Santos, J.E., Hogg, N., Cannon, R.O., 3rd, Schechter, A.N., and Gladwin, M.T. (2002). Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 8, 1383-1389.
94. Rolla, S., Ingoglia, G., Bardina, V., Silengo, L., Altruda, F., Novelli, F., and Tolosano, E. (2013). Acutephase protein hemopexin is a negative regulator of Th17 response and experimental autoimmune encephalomyelitis development. J Immunol 191, 5451-5459.
95. Rother, R.P., Bell, L., Hillmen, P., and Gladwin, M.T. (2005). The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 293, 1653-1662.
96. Schaer, C.A., Deuel, J.W., Bittermann, A.G., Rubio, I.G., Schoedon, G., Spahn, D.R., Wepf, R.A., Vallelian, F., and Schaer, D.J. (2013a). Mechanisms of haptoglobin protection against hemoglobin peroxidation triggered endothelial damage. Cell Death Differ 20, 1569-1579.
97. Schaer, C.A., Laczko, E., Schoedon, G., Schaer, D.J., and Vallelian, F. (2013b). Chloroquine interference with hemoglobin endocytic trafficking suppresses adaptive heme and iron homeostasis in macrophages: the paradox of an antimalarial agent. Oxid Med Cell Longev 2013, 870472.
98. Schaer, C.A., Vallelian, F., Imhof, A., Schoedon, G., and Schaer, D.J. (2007). CD163-expressing monocytes constitute an endotoxin-sensitive Hb clearance compartment within the vascular system. J Leukoc Biol 82, 106-110.
99. Schaer, D.J., Boretti, F.S., Hongegger, A., Poehler, D., Linnscheid, P., Staege, H., Muller, C., Schoedon, G., and Schaffner, A. (2001). Molecular cloning and characterization of the mouse CD163 homologue, a highly glucocorticoid-inducible member of the scavenger receptor cysteine-rich family. Immunogenetics 53, 170-177.
100. Schaer, D.J., Boretti, F.S., Schoedon, G., and Schaffner, A. (2002). Induction of the CD163-dependent haemoglobin uptake by macrophages as a novel anti-inflammatory action of glucocorticoids. Br J Haematol 119, 239-243.
101. Schaer, D.J., Buehler, P.W., Alayash, A.I., Belcher, J.D., and Vercellotti, G.M. (2012). Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood.
102. Schaer, D.J., Schaer, C.A., Buehler, P.W., Boykins, R.A., Schoedon, G., Alayash, A.I., and Schaffner, A. (2006). CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin. Blood 107, 373-380.
103. Schaer, D.J., Schleiffenbaum, B., Kurrer, M., Imhof, A., Bachli, E., Fehr, J., Moller, H.J., Moestrup, S.K., and Schaffner, A. (2005). Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J Haematol 74, 6-10.
104. Shen, H., Song, Y., Colangelo, C.M., Wu, T., Bruce, C., Scabia, G., Galan, A., Maffei, M., and Goldstein, D.R. (2012). Haptoglobin activates innate immunity to enhance acute transplant rejection in mice. J Clin Invest 122, 383-387.
105. Silverman, T.A., and Weiskopf, R.B. (2009). Hemoglobin-based oxygen carriers: current status and future directions. Transfusion 49, 2495-2515.
106. Silverman, T.A., Weiskopf, R.B., Planning, C., and The, S. (2009). Hemoglobin-based oxygen carriers: current status and future directions. Anesthesiology 111, 946-963.
107. Spiller, F., Costa, C., Souto, F.O., Vinchi, F., Mestriner, F.L., Laure, H.J., Alves-Filho, J.C., Freitas, A., Rosa, J.C., Ferreira, S.H., Altruda, F., Hirsch, E., Greene, L.J., Tolosano, E., and Cunha, F.Q. (2011). Inhibition of neutrophil migration by hemopexin leads to increased mortality due to sepsis in mice. Am J Respir Crit Care Med 183, 922-931.
108. Subramanian, K., Du, R., Tan, N.S., Ho, B., and Ding, J.L. (2013). CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms. J Immunol 190, 5267-5278.
109. Tanaka, K., Kanamori, Y., Sato, T., Kondo, C., Katayama, Y., Yada, I., Yuasa, H., and Kusagawa, M. (1991). Administration of haptoglobin during cardiopulmonary bypass surgery. ASAIO Trans 37, M482-483.
110. Tolosano, E., Hirsch, E., Patrucco, E., Camaschella, C., Navone, R., Silengo, L., and Altruda, F. (1999). Defective recovery and severe renal damage after acute hemolysis in hemopexindeficient mice. Blood 94, 3906-3914.
111. Vallelian, F., Pimenova, T., Pereira, C.P., Abraham, B., Mikolajczyk, M.G., Schoedon, G., Zenobi, R., Alayash, A.I., Buehler, P.W., and Schaer, D.J. (2008). The reaction of hydrogen peroxide with hemoglobin induces extensive alpha-globin crosslinking and impairs the interaction of hemoglobin with endogenous scavenger pathways. Free Radic Biol Med 45, 1150-1158.
112. Vallelian, F., Schaer, C.A., Kaempfer, T., Gehrig, P., Duerst, E., Schoedon, G., and Schaer, D.J. (2010). Glucocorticoid treatment skews human monocyte differentiation into a hemoglobinclearance phenotype with enhanced heme-iron recycling and antioxidant capacity. Blood 116, 5347-5356.
113. Vinchi, F., De Franceschi, L., Ghigo, A., Townes, T., Cimino, J., Silengo, L., Hirsch, E., Altruda, F., and Tolosano, E. (2013). Hemopexin therapy improves cardiovascular function by preventing heme-induced endothelial toxicity in mouse models of hemolytic diseases. Circulation 127, 1317-1329.
114. Vinchi, F., Gastaldi, S., Silengo, L., Altruda, F., and Tolosano, E. (2008). Hemopexin prevents endothelial damage and liver congestion in a mouse model of heme overload. Am J Pathol 173, 289-299.
115. Wagener, F.A., Eggert, A., Boerman, O.C., Oyen, W.J., Verhofstad, A., Abraham, N.G., Adema, G., Van Kooyk, Y., De Witte, T., and Figdor, C.G. (2001). Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase. Blood 98, 1802-1811.
116. Weaver, L.K., Hintz-Goldstein, K.A., Pioli, P.A., Wardwell, K., Qureshi, N., Vogel, S.N., and Guyre, P.M. (2006). Pivotal advance: activation of cell surface Toll-like receptors causes shedding of the hemoglobin scavenger receptor CD163. J Leukoc Biol 80, 26-35.
117. Zwadlo, G., Voegeli, R., Schulze Osthoff, K., and Sorg, C. (1987). A monoclonal antibody to a novel differentiation antigen on human macrophages associated with the down-regulatory phase of the inflammatory process. Exp Cell Biol 55, 295-304.