Mechanisms of toxicity and modulation of hemoglobin-based oxygen carriers

Shock

Volumn 52, Issue 1S, 2019, Pages 41-49

  Alayash, Abdu I ^a  

^a CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

Author keywords

Hemoglobin; hemoglobin based oxygen carriers; oxidative toxicity

Indexed keywords

ASCORBIC ACID; BLOOD SUBSTITUTE; CARBON MONOXIDE; DIASPIRIN CROSSLINKED HEMOGLOBIN; HEME; HEMOGLOBIN; HEMOGLOBIN BASED OXYGEN CARRIER; HEMOGLOBIN GLUTAMER 256; HEMOGLOBIN RAFFIMER; LIVER ENZYME; OXYGEN; PANCREAS ENZYME; POLYETHYLENE GLYCOL MALEIMIDE; POLYETHYLENE GLYCOL SUCCINIMIDYL CARBONATE; POLYMERIZED HEMOGLOBIN; PROTEIN; PYRIDOXAL 5 PHOSPHATE; RECOMBINANT HEMOGLOBIN; UNCLASSIFIED DRUG;

DRUG SAFETY; HUMAN; MOLECULAR SIZE; OXYGEN AFFINITY; PHYSICAL CHEMISTRY; REVIEW; ANIMAL; BLOOD; METABOLISM; OXIDATION REDUCTION REACTION;

ANIMALS; BLOOD SUBSTITUTES; HEMOGLOBINS; HUMANS; OXIDATION-REDUCTION; OXYGEN;

EID: 85072133781     PISSN: 10732322     EISSN: 15400514     Source Type: Journal    
DOI: 10.1097/SHK.0000000000001044     Document Type: Review

References (81)

1. Alayash AI: Setbacks in blood substitutes research and development: A biochemical perspective. Clin Lab Med 30:381-389, 2010.
2. Nelson D, Azari M, Brown R, Burhop K, Bush S, Catarello J, Chuang H, Downing C, Estep T, Loewen A, et al.: Preparation and characterization of diaspirin cross-linked hemoglobin solutions for preclinical studies. Biomater Artif Cells Immobil Biotechnol 20:423-427, 1992.
3. Sloan EP, Koenigsberg M, Weir WB, Clark JM, O'Connor R, Olinger M, Cydulka R: Emergency resuscitation of patients enrolled in the US Diaspirin Cross-linked Hemoglobin (DCLHb). Clinical Efficacy Trial Prehosp Disaster Med 1:54-61, 2015.
4. Hoffman SJ, Looker DL, Roehrich JM, Cozart PE, Durfee SL, Tedesco JL, Stetler GL: Expression of fully functional tetrameric human hemoglobin in coli. Proc Natl Acad Sci USA 87:8521-8525, 1990.
5. Sloan EP, Koenigsberg M, Clark JM, Weir WB, Philbin N: Shock index and prediction of traumatic hemorrhagic shock 28-day mortality: Data from the DCLHb resuscitation clinical trials. West J Emerg Med 7:795-802, 2014.
6. D'Agnillo F, Alayash AI: Site-specific modifications and toxicity of blood substitutes: The case of diaspirin cross-linked hemoglobin. Adv Drug Deliv Rev 40:199-212, 2000.
7. Washita Y: Relationship between chemical properties and biological properties of pyridoxalated hemoglobin polyoxyethylene. Biomat Artif Cell Immbol 20:299-307, 1992.
8. Kinasewitz GT, Privalle CT, Imm A, Steingrub JS, Malcynski JT, Balk RA, DeAngelo J: Multicenter, randomized, placebo-controlled study of the nitric oxide scavenger pyridoxalated hemoglobin polyoxyethylene in distributive shock. Crit Care Med 36:1999-2007, 2008.
9. Winslow RM: MP4, a new nonvasoactive polyethylene glycol-hemoglobin conjugate. Artif Organs 9:800-806, 2004.
10. Olofsson CI, Gorecki AZ, Dirksen R, Kofranek I, Majewski JA, Mazurkiewicz T, Jahoda D, Fagrell B, Keipert PE, Hardiman YJ, et al.: Study 6084 clinical investigators. Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: A randomized, double-blind, multicenter study. Anesthesiology 114:1048-1063, 2011.
11. Weiskopf RB: Hemoglobin-based oxygen carriers: Disclosed history and theway ahead: The relativity of safety. Anesth Analg 119:758-760, 2014.
12. Gould SA, Moore EE, Hoyt DB, Burch JM, Haenel JB, Garcia J, DeWoskin R, Moss GS: The first randomized trial of human polymerized hemoglobin as a blood substitute in acute trauma and emergent surgery. J Am Coll Surg 187:113-122, 1998.
13. Gould SA, Moore EE, Hoyt DB, Burch JM, Ness PM, Norris EJ, Carson JL, Hides GA, Freeman IH, DeWoskin R, et al.: The life sustaining capacity of human polymerized hemoglobin when red cells might be unavailable. J Am Coll Surg 195:445-452, 2002.
14. Levy JH, Goodnough LT, Grelich PE, Parr GV, Stewart RW, Gratz I, Wahr J, Williams J, Comunale ME, Doblar D, et al.: Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: Results of a randomized, double-blind trial. J Thorac Cardiovasc Surg 124:35-42, 2002.
15. Sprung J, Kindscher JD, Wahr JA, Levy JH, Monk TG, Moritz MW, O'Hara PJ: The use of bovine hemoglobin glutamer-250 (Hemopure) in surgical patients: Results of a multicenter, randomized, single-blinded trial. Anesth Analg 94:799-808, 2002.
16. Boykins RA, Buehler PW, Jia Y, Venable R, Alayash AI: O-raffinose crosslinked hemoglobin lacks site-specific chemistry in the central cavity: Structural and functional consequences of beta93Cys modification. Proteins 59:840-855, 2005.
17. Carmichael FJ, Ali AC, Campbell JA, Langlois SF, Biro GP, Willan AR, Pierce CH, Greenburg AG: A phase I study of oxidized raffinose cross-linked human hemoglobin. Crit Care Med 28:2283-2292, 2000.
18. Hill S, Gottschalk LI, Grichnik K: Safety and preliminary efficacy of hemoglobin raffimer for patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth 16:695-702, 2002.
19. Silverman TA, Weiskopf RB: Hemoglobin-based oxygen carriers: Current status and future directions. Transfusion 49:2495-2515, 2009.
20. Buehler PW, Alayash AI: Toxicities of hemoglobin solutions: In search of invitro and in-vivo model systems. Transfusion 44:1516-1530, 2004.
21. Alayash AI: Hemoglobin-based blood substitutes: Oxygen carriers, pressor agents, or oxidants Nat Biotechnol 17:545-549, 1999.
22. Alayash AI, Cashon RE: Hemoglobin and free radicals: Implications for the development of a safe blood substitute. Mol Med Today 1:122-127, 1995.
23. Reeder BJ: The redox activity of hemoglobins: From physiologic functions to pathologic mechanisms. Antioxid Redox Signal 13:1087-1123, 2010.
24. Buehler PW, D'Agnillo F, Hoffman V, Alayash AI: 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, 2007.
25. Hess JR, MacDonald VW: Systemic and pulmonary hypertension after resuscitation with cell-free hemoglobin. J Appl Physiol 74:1769-1778, 1993.
26. Burhop K, Gordon D, Estep T: Review of hemoglobin-induced myocardial lesions. Artif Cells Blood Substit Immobil Biotechnol 32:353-374, 2004.
27. Rentsendorj O, Zhang X, Williams MC, Buehler PW, D'Agnillo F: Transcriptional suppression of renal antioxidant enzyme systems in guinea pigs exposed to polymerized cell-free hemoglobin. Toxics 4(1). pii: 6.
28. Weiskopf RB, Beliaev AM, Shandler A, Guinn NR, Cap AP, Ness PM, Silverman TA: Addressing the unmet need of life-threatening anemia with hemoglobin-based oxygen carriers. Transfusion 57:207-214, 2017.
29. Olson JS, Foley EW, Rogge C, Tsai AL, Doyle MP, Lemon DD: NO scavenging and the hypertensive effect of hemoglobin-based blood substitutes. Free Radic Biol Med 36:685-697, 2004.
30. Zhang R, Hess DT, Qian Z, Hausladen AF, Fonseca F, Chaube R, Reynolds JD, Stamler JS: Hemoglobin bCys93 is essential for cardiovascular function and integrated response to hypoxia. Proc Natl Acad Sci USA 112:6425-6430, 2015.
31. Kim-Shapiro DB, Gladwin MT: Mechanisms of nitrite bioactivation. Nitric Oxide 38:58-68, 2014.
32. Moon-Massat P, Scultetus A, Arnaud F, Brown A, Haque A, Saha B, Kim B, Sagini E, McGwin G Jr, Auker C, et al.: Effect of HBOC-201 and sodium nitrite resuscitation after uncontrolled haemorrhagic shock in swine. Injury 43:638-647, 2012.
33. Baek JH, Zhang X, Williams MC, Hicks W, Buehler PW, D'Agnillo F: Sodium nitrite potentiates renal oxidative stress and injury in hemoglobin exposed guinea pigs. Toxicology 333:89-99, 2015.
34. Machado RJ, Barst NA, Yovetich KL, Hassell GJ, Kato GJ, Gordeuk VR, Gibbs JS, Little JA, Schraufnagel DE, Krishnamurti L, et al.: Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRVand low exercise capacity. Blood 118:855-864, 2011.
35. Schaer DJ, Buehler PW, Alayash AI, Belcher JD, Vercellotti GM: Hemolysis and free hemoglobin revisited: Exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 121:1276-1284, 2013.
36. Belcher JD, Chen C, Nguyen J, Milbauer L, Abdulla F, Alayash AI, Smith A, Nath KA, Hebbel RP, Vercellotti GM: Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123:377-390, 2014.
37. Mollan TL, Alayash AI: Redox reactions of hemoglobin: Mechanisms of toxicity and control. Antioxid Redox Signal 18:2251-2253, 2013.
38. Kassa T, Jana S, Strader MB, Meng F, Jia Y, Wilson MT: Alayash, A. I. Sickle cell hemoglobin in the ferryl state promotes bCys-93 oxidation and mitochondrial dysfunction in epithelial lung cells (E10). J Biol Chem 289:22342-22357, 2015.
39. Jia Y, Buehler PW, Boykins RA, Venable RM, Alayash AI: Structural basis of peroxide-mediated changes in human hemoglobin: A novel oxidative pathway. J Biol Chem 282:4894-4907, 2007.
40. Kassa T, Jana S, Meng F, Alayash AI: Differential heme release from various hemoglobin redox states and the upregulation of cellular heme oxygenase-1. FEBS Open Bio 6:876-884, 2016.
41. Bonaventura C, Henkens R, Alayash AI, Crumbliss AL: Allosteric effects on oxidative and nitrosative reactions of cell-free hemoglobins. IUBMB Life 59:498-505, 2007.
42. Bonaventura C, Henkens R, Alayash AI, Banerjee S, Crumbliss AL: Molecular controls of the oxygenation and redox reactions of hemoglobin. Antioxid Redox Signal 18:2298-2313, 2013.
43. Nagababu E, Ramasamy S, Rifkind JM, Jia Y, Alayash AI: Site-specific crosslinking of human and bovine hemoglobins differentially alters oxygen binding and redox side reactions producing rhombic heme and heme degradation. Biochemistry 41:7407-7415, 2002.
44. D'Agnillo F, Chang TM: Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties. Nat Biotechnol 16:667-671, 1998.
45. Vandegriff KD, Malavalli A, Minn C, Jiang E, Lohman J, Young MA, Samaja M, Winslow RM: Oxidation and haem loss kinetics of poly(ethylene glycol)-conjugated haemoglobin (MP4): Dissociation between in vitro and in vivo oxidation rates. Biochem J 3:463-471, 2006.
46. Lee R, Neya K, Svizzero TA, Vlahakes GJ: Limitations of the efficacy of hemoglobin-based oxygen-carrying solutions. J Appl Physiol 79:236-242, 1985.
47. Manalo DJ, Buehler PW, Baek JH, Butt O, D'Agnillo, Alayash AI: Acellular haemoglobin attenuates hypoxia-inducible factor-1alpha (HIF-1alpha) and its target genes in haemodiluted rats. Biochem J 414:461-469, 2008.
48. Baek JH, D'Agnillo F, Vallelian F, Pereira CP, Williams MC, Jia Y, Schaer DJ, Buehler PW: 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, 2012.
49. Mollan TL, Banerjee S, Wu G, Parker Siburt CJ, Tsai AL, Olson JS, Weiss MJ, Crumbliss AL, Alayash AI: A-Hemoglobin stabilizing protein (AHSP)markedly decreases the redox potential and reactivity of a-subunits of human HbA with hydrogen peroxide. J Biol Chem 288:4288-4298, 2013.
50. Buehler PW, Karnaukhova E, Gelderman MP, Alayash AI: Blood aging, safety, and transfusion: Capturing the "radical" menace. Antioxid Redox Signal 14:1713-1728, 2011.
51. Alayash AI: Haptoglobin: Old protein with new functions. Clin Chim Acta 412:493-498, 2011.
52. Alayash AI, Andersen CB, Moestrup SK, Bülow L: Haptoglobin: The hemoglobin detoxifier in plasma. Trends Biotechnol 31:2-3, 2013.
53. Reeder BJ, Grey M, Silaghi-Dumitrescu RL, Svistunenko DA, Bülow L, Cooper CE, Wilson MT: Tyrosine residues as redox cofactors in human hemoglobin: Implications for engineering nontoxic blood substitutes. J Biol Chem 283:30780-33087, 2008.
54. Cooper CE, Schaer DJ, Buehler PW, Wilson MT, Reeder BJ, Silkstone G, Svistunenko DA, Bulow L, Alayash AI: Haptoglobin binding stabilizes hemoglobin ferryl iron and the globin radical on tyrosine b145. Antioxid Redox Signal 18:2264-2267, 2013.
55. Mollan TL, Jia Y, Banerjee S, Wu G, Kreulen RT, Tsai AL, Olson JS, Crumbliss AL, Alayash AI: Redox properties of human hemoglobin in complex with fractionated dimeric and polymeric human haptoglobin. Free Radic Biol Med 69:265-277, 2014.
56. H Jia Y, Wood F, Buehler PW, Alayash AI: Haptoglobin preferentially binds b but not a subunits cross-linked hemoglobin tetramers with minimal effects on ligand and redox reactions. PLoS One 8(3):e59841, 2013.
57. Smith A, McCulloh RJ: Hemopexin and haptoglobin: Allies against heme toxicity from hemoglobin not contenders. Front Physiol 6:187, 2015.
58. Hrkal Z, Vodrazka Z, Kalousek I: Transfer of heme from ferrihemoglobin and ferrihemoglobin isolated chains to hemopexin. Eur J Biochem 43: 73-78, 1974.
59. Vercellotti GM, Zhang P, Nguyen J, Abdulla F, Chen C, Nguyen P, Nowotny C, Steer CJ, Smith A, Belcher JD: Overexpression of hemopexin inhibits inflammation and vascular stasis in murine models of sickle cell disease. Mol Med 22:437-451, 2016.
60. Silva D G.H., Belini E Jr, Alves de Almeida E, Regina C, Bonini-Domingos CR: Oxidative stress in sickle cell disease: An overview of erythrocyte redox metabolism and current antioxidant therapeutic strategies. Free Rad Biol Med 65:1101-1109, 2013.
61. Marangon K, Devaraj S, Tirosh O, Packer L, Jialal I: Comparison of the effect of a-lipoic acid and a-tocopherol supplementation on measures of oxidative stress. Free Radic Biol Med 27:1114-1121, 1999.
62. Arruda MM, Mecabo G, Rodrigues CA, Matsuda SS, Rabelo IB, Figueiredo MS: Antioxidant vitamins C and E supplementation increases markers of haemolysis in sickle cell anaemia patients: A randomized, double-blind, placebo-controlled trial. Br J Haematol 160:688-700, 2013.
63. Muskiet FA, Muskiet FD, Meiborg G, Schermer JG: Supplementation of patients with homozygous sickle cell disease with zinc, alpha-tocopherol, vitamin C, soybean oil, and fish oil. Am J Nutr 54:736-744, 1991.
64. Dunne J, Caron A, Menu P, Alayash AI, Buehler PW, Cooper CE: Ascorbate removes key precursors to oxidative damage by cell-free haemoglobin in vitro and in vivo. Biochem J 399:513-524, 2006.
65. Cooper CE, Silaghi-Dumitrescu R, Rukengwa M, Alayash AI, Buehler PW: Peroxidase activity of hemoglobin towards ascorbate and urate: A synergistic protective strategy against toxicity of Hemoglobin-Based Oxygen Carriers (HBOC). Biochim Biophys Acta 1784:1415-1420, 2008.
66. Silkstone G, G. Silkstone R.S., Wilson MT, Simons M, Bülow L, Kallberg K, Ratanasopa K, Ronda L, Mozzarelli A, Reeder BJ, et al.: Engineering tyrosine electron transfer pathways decreases oxidative toxicity in hemoglobin: Implications for blood substitute design. Biochem J 473:3371-3383, 2016.
67. Fitzgerald MC, Chan JY, Ross AW, Liew SM, ButtWW, Baguley D, Salem HH, Russ MK, Deasy C, Martin KE, et al.: A synthetic haemoglobin-based oxygen carrier and the reversal of cardiac hypoxia secondary to severe anaemia following trauma. Med J Aust 194:471-473, 2011.
68. Abraham B, Hicks W, Jia Y, Baek JH, Miller JL, Alayash AI: Isolated Hb Providence beta82Asn and beta82Asp fractions are more stable than native HbA0 under oxidative stress conditions. Biochemistry 50:9752-9766, 2011.
69. WeickertMJ, Pagratis M, Glascock CB, Blackmore R: Amutation that improves soluble recombinant hemoglobin accumulation in Escherichia coli in heme excess. Appl Environ Microbiol 65:640-647, 1999.
70. Reeder BJ, Grey M, Silaghi-Dumitrescu RL, Svistunenko DA, Bulow L, Cooper CE, Wilson MT: Tyrosine residues as redox cofactors in human hemoglobin: Implications for engineering nontoxic blood substitutes. J Biol Chem 283:30780-30787, 2008.
71. Araujo JA: HO-1 and CO: Fighters vs sickle cell disease Blood 122:2535-2536, 2013.
72. Ji X, Damera K, Zheng Y, Yu B, Otterbein LE, Wang B: Toward carbon monoxide-based therapeutics: Critical drug delivery and developability issues. J Pharm Sci 105:406-416, 2016.
73. Vandegriff KD, Young MA, Lohman J, Bellelli A, Samaja M, Malavalli A, Winslow RM: CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats. Br J Pharmacol 154:1649-1661, 2008.
74. Belcher JD, Young M, Chen C, Nguyen J, Burhop K, Tran P, Vercellotti GM: MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice. Blood 122:2757-2764, 2013.
75. Nho K, Glower D, Bredehoeft S, Shankar H, Shorr R, Abuchowski A: PEGbovine hemoglobin: Safety in a canine dehydrated hypovolemic-hemorrhagic shock model. Biomater Artif Cells Immobil Biotechnol 20:511-524, 1992.
76. Zhang J, Cao S, Kwansa H, Crafa D, Kibler KK, Koehler RC: Transfusion of hemoglobin-based oxygen carriers in the carboxy state is beneficial during transient focal cerebral ischemia. J Appl Physiol 113:1709-1717, 2012.
77. Abuchowski A: PEGylated bovine carboxyhemoglobin (SANGUINATETM): Results of clinical safety testing and use in patients. Adv Exp Med Biol 876:461-467, 2016.
78. Hsia CJ, Ma L: A hemoglobin-based multifunctional therapeutic: Polynitroxylated pegylated hemoglobin. Artif Organs 36:215-220, 2012.
79. Brockman EC, Bayr H, Blasiole B, Shein SL, Fink EL, Dixon C, Clark RS, Vagni VA, Ma L, Hsia CJ, et al.: Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice. J Cereb Blood Flow Metab 33:1457-1464, 2013.
80. Marchand A, Crepin N, Roulland I, Semence F, Domergue V, Zal F, Polard V, Coquerel A: Application of HBOCs electrophoretic method to detect a new blood substitute derived from the giant extracellular haemoglobin of lugworm. Drug Test Anal 9(11-12):1762-1767, 2017.
81. Le Gall T, Polard V, Rousselot M, Lotte A, Raouane M, Lehn P, Opolon P, Leize E, Deutsch E, Zal F, et al.: In vivo biodistribution and oxygenation potential of a new generation of oxygen carrier. J Biotechnol 187:1-9, 2014.